Compounds for the modulation of PPARgamma activity

ABSTRACT

Modulators of PPARγ activity are provided which are useful in pharmaceutical compositions and methods for the treatment of conditions such as type II diabetes and obesity.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application is related to U.S. Ser. No. 60/073,042, filedJan. 29, 1998, and U.S. Ser. No. 09/234,327, filed Jan. 20, 1999, andclaims the benefit of U.S. Ser. No. 60/141,672, filed Jun. 30, 1999.This application is also related to PCT application ______, filed Jun.28, 2000 (Attorney Docket 018781-002710PC). The disclosures of each ofthe above being incorporated herein by reference in their entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

[0002] The invention described herein was not made with the aid of anyfederally sponsored grants.

FIELD OF THE INVENTION

[0003] The present invention relates to compounds that modulate thePPARγ receptor and are useful in the diagnosis and treatment of type IIdiabetes (and complications thereof), hypercholesterolemia (and relateddisorders associated with abnormally high or low plasma lipoprotein ortriglyceride levels) and inflammatory disorders.

BACKGROUND OF THE INVENTION

[0004] The peroxisome proliferator-activated receptors (PPARs) aretransducer proteins belonging to the steroid/thyroid/retinoid receptorsuperfamily. The PPARs were originally identified as orphan receptors,without known ligands, but were named for their ability to mediate theplelotropic effects of fatty acid peroxisome proliferators. Thesereceptors function as ligand-regulated transcription factors thatcontrol the expression of target genes by binding to their responsiveDNA sequence as heterodimers with RXR. The target genes encode enzymesinvolved in lipid metabolism and differentiation of adipocytes.Accordingly, the discovery of transcription factors involved incontrolling lipid metabolism has provided insight into regulation ofenergy homeostasis in vertebrates, and further provided targets for thedevelopment of therapeutic agents for disorders such as obesity,diabetes and dyslipidemia.

[0005] PPARγ is one member of the nuclear receptor superfamily ofligand-activated transcription factors and has been shown to beexpressed in an adipose tissue-specific manner. Its expression isinduced early during the course of differentiation of severalpreadipocyte cell lines. Additional research has now demonstrated thatPPARγ plays a pivotal role in the adipogenic signaling cascade. PPARγalso regulates the ob/leptin gene which is involved in regulating energyhomeostasis, and adipocyte differentiation which has been shown to be acritical step to be targeted for anti-obesity and diabetic conditions.

[0006] In an effort to understand the role of PPARγ in adipocytedifferentiation, several investigators have focused on theidentification of PPARγ activators. One class of compounds, thethiazolidinediones, which were known to have adipogenic effects onpreadipocyte and mesenchymal stem cells in vitro, and antidiabeticeffects in animal models of non-insulin-dependent diabetes mellitus(NIDDM) were also demonstrated to be PPARγ-selective ligands. Morerecently, compounds that selectively activate murine PPARγ were shown topossess in vivo antidiabetic activity in mice.

[0007] Despite the advances made with the thiazolidinedione class ofantidiabetes agents, unacceptable side effects have limited theirclinical use. Accordingly, there remains a need for potent, selectiveactivators of PPARγ which will be useful for the treatment of NIDDM andother disorders related to lipid metabolism and energy homeostasis.Still further, compounds that block PPARγ activity would be useful forinterfering with the maturation of preadipocytes into adipocytes andthus would be useful for the treatment of obesity and related disordersassociated with undesirable adipocyte maturation. Surprisingly, thepresent invention provides compounds that are useful as activators aswell as antagonists of PPARγ activity and compositions containing them,along with methods for their use.

SUMMARY OF THE INVENTION

[0008] In one aspect, the present invention provides methods ofmodulating conditions which are mediated by PPARγ. The methods typicallyinvolve contacting the host with a PPARγ-modulating amount of a compoundhaving the formula:

[0009] in which the symbol Ar¹ represents a substituted or unsubstitutedaryl group; the letter X represents a divalent linkage selected fromsubstituted or unsubstituted (C₁-C₆)alkylene, substituted orunsubstituted (C₁-C₆)alkylenoxy, substituted or unsubstituted(C₁-C₆)alkylenamino, substituted or unsubstituted(C₁-C₆)alkylene-S(O)_(k), —O—, —C(O)—, —N(R¹¹)—, —N(R¹¹)C(O)—,—S(O)_(k)— and a single bond, in which R¹¹ is a member selected fromhydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and aryl(C₁-C₄)alkyl and thesubscript k is an integer of from 0 to 2. The letter Y, in the aboveformula represents a divalent linkage selected from substituted orunsubstituted (C₁-C₆)alkylene, —O—, —C(O)—, —N(R¹²)—S(O)_(m)—,—N(R¹²)S(O)_(m)—N(R¹³)—, —N(R¹²)C(O)—, —S(O)_(n)—, a single bond, andcombinations thereof, in which R¹² and R¹³ are members independentlyselected from hydrogen, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₂-C₈)heteroalkyl and substituted orunsubstituted aryl(C₁-C₄)alkyl; and the subscripts m and n areindependently integers of from 0 to 2.

[0010] The symbol R¹ represents a member selected from hydrogen,halogen, cyano, nitro, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, —CO₂R¹⁴,—C(O)NR¹⁵R¹⁶, —C(O)R¹⁴, —S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—OR¹⁷,—O—C(O)—R¹⁷, —O—C(O)—NR¹⁵R¹⁶, —N(R¹⁴)—C(O)—NR¹⁵R¹⁶, —N(R¹⁴)—C(O)—R¹⁷ and—N(R¹⁴)—C(O)—OR¹⁷, in which R¹⁴ is a member selected from hydrogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from hydrogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, aryl, and aryl(C₁-C₄)alkyl, or taken together withthe nitrogen to which each is attached form a 5-, 6- or 7-membered ring;and R¹⁷ is a member selected from hydrogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl. In each of thedescriptions of, for example, alkyl, alkoxy and heteroalkyl, the groupscan be substituted or unsubstituted.

[0011] The symbol R² represents a substituted or unsubstituted arylgroup. Preferably, R² represents a phenyl, naphthyl, pyridazinyl orpyridyl group. More preferably, R² is a phenyl, naphthyl, pyridazinyl orpyridyl group substituted with from 0-3 substituents selected fromhalogen, —OCF₃, —OH, —O(C₁-C₈)alkyl, —CN, —CF₃, —C(O)—(C₁-C₈)alkyl,—(C₁-C₈)alkyl and —NH₂.

[0012] The symbol R³ represents a halogen, cyano, nitro or a substitutedor unsubstituted (C₁-C₈)alkoxy group.

[0013] In another aspect, the present invention provides compounds ofthe formula above, as well as pharmaceutical compositions containing thecompounds described above.

DETAILED DESCRIPTION OF THE INVENTION

[0014] Abbreviations and Definitions:

[0015] The following abbreviations are used herein: PPARγ: peroxisomeproliferator-activated receptor γ; NIDDM: non-insulin-dependent diabetesmellitus; Et₃N: triethylamine; MeGH: methanol; and DMSO:dimethylsulfoxide.

[0016] The term “alkyl,” by itself or as part of another substituent,means, unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). Examples of saturated hydrocarbon radicalsinclude groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers. The term “alkyl,” unless otherwise noted, is also meant toinclude those derivatives of alkyl defined in more detail below as“heteroalkyl,” “cycloalkyl” and “alkylene.” The term “alkylene” byitself or as part of another substituent means a divalent radicalderived from an alkane, as exemplified by —CH₂CH₂CH₂CH₂—. Typically, analkyl group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms.

[0017] The term “heteroalkyl,” by itself or in combination with anotherterm, means, unless otherwise stated, a stable straight or branchedchain, or cyclic hydrocarbon radical, or combinations thereof,consisting of the stated number of carbon atoms and from one to threeheteroatoms selected from the group consisting of O, N, Si and S, andwherein the nitrogen and sulfur atoms are optionally oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) O,N and S may be placed at any interior position of the heteroalkyl group.The heteroatom Si may be placed at any position of the heteroalkylgroup, including the position at which the alkyl group is attached tothe remainder of the molecule. Examples include —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—, CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Also included in the term“heteroalkyl” are those radicals described in more detail below as“heteroalkylene” and “heterocycloalkyl.” The term “heteroalkylene” byitself or as part of another substituent means a divalent radicalderived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini. Still further, for alkyleneand heteroalkylene linking groups, as well as all other linking groupprovided in the present invention, no orientation of the linking groupis implied.

[0018] The terms “cycloalkyl” and “heterocycloalkyl”, by themselves orin combination with other terms, represent, unless otherwise stated,cyclic versions of “alkyl” and “heteroalkyl”, respectively.Additionally, for heterocycloalkyl, a heteroatom can occupy the positionat which the heterocycle is attached to the remainder of the molecule.Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkylinclude 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

[0019] The terms “halo” or “halogen,” by themselves or as part ofanother substituent, mean, unless otherwise stated, a fluorine,chlorine, bromine, or iodine atom. Additionally, terms such as“fluoroalkyl,” are meant to include monofluoroalkyl and polyfluoroalkyl.

[0020] The term “aryl,” employed alone or in combination with otherterms (e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwisestated, an aromatic substituent which can be a single ring or multiplerings (up to three rings) which are fused together or linked covalently.The rings may each contain from zero to four heteroatoms selected fromN, O, and 5, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. The arylgroups that contain heteroatoms may be referred to as “heteroaryl” andcan be attached to the remainder of the molecule through a heteroatomNon-limiting examples of aryl groups include phenyl, 1-naphthyl,2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 2-benzothiazolyl, 5-benzothiazolyl, 2-benzoxazolyl,5-benzoxazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl,5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl, and6-quinolinyl. Substituents for each of the above noted aryl ring systemsare selected from the group of acceptable substituents described below.The term “arylalkyl” is meant to include those radicals in which an arylgroup is attached to an alkyl group (e.g., benzyl, phenethyl,pyridylmethyl and the like) or a heteroalkyl group (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

[0021] Each of the above terms (e.g., “alkyl,” “heteroalkyl” and “aryl”)are meant to include both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

[0022] Substituents for the alkyl and heteroalkyl radicals (includingthose groups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′,—CO₂R′, CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —CN and —NO₂ in a number ranging from zero to (2N+1), whereN is the total number of carbon atoms in such radical. R′, R″ and R″′each independently refer to hydrogen, unsubstituted(C₁-C₈)alkyl andheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C₁-C₄)alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.For example, —NR′R″ is meant to include 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like). Preferably, the alkylgroups (and related alkoxy, heteroalkyl, etc.) are unsubstituted or have1 to 3 substituents selected from halogen, —OR′, ═O, —NR′R″, —SR′,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —NR″C(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—CN and —NO₂. More preferably, the alkyl and related groups have 0, 1 or2 substituents selected from halogen, —OR′, ═O, —NR′R″, —SR′, —CO₂R′,—CONR′R″, —NR″C(O)R′, —CN and —NO₂.

[0023] Similarly, substituents for the aryl groups are varied and areselected from halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂——CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R″′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, (C₁-C₈)alkyl and heteroalkyl,unsubstituted aryl, (unsubstituted aryl)-(C₁-C₄)alkyl, and(unsubstituted aryl)oxy-(C₁-C₄)alkyl. Preferably, the aryl groups areunsubstituted or have from 1 to 3 substituents selected from halogen,—OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂— —CO₂R′, —CONR′R″, —C(O)R′,—NR″C(O)R′, —S(O)₂R′, —S(O)₂NR′R″, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl. Still more preferably, the aryl groups have 0, 1or 2 substituents selected from halogen, —OR′, —NR′R″, —SR′, —R′, —CN,—NO₂— —CO₂R′, —CONR′R″, —NR″C(O)R′, —S(O)₂R′, —S(O)₂NR′R″,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl.

[0024] Two of the substituents on adjacent atoms of the aryl ring mayoptionally be replaced with a substituent of the formula wherein T and Uare independently —NH—, —O—, —CH₂— or a single bond, and q is an integerof from 0 to 2. Alternatively, two of the substituents on adjacent atomsof the aryl ring may optionally be replaced with a substituent of theformula —A—(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—,—NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl ring may optionally bereplaced with a substituent of the formula —(CH₂), —X—(CH₂)_(t)—, wheres and t are independently integers of from 0 to 3, and X is —O—, —NR′—,—S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituent R′ in —NR′— and—S(O)₂NR′— is selected from hydrogen or unsubstituted (C₁-C₆)alkyl.

[0025] As used herein, the term “heteroatom” is meant to include oxygen(O), nitrogen (N), sulfur (S) and silicon (Si).

[0026] The term “pharmaceutically acceptable salts” is meant to includesalts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

[0027] The neutral forms of the compounds may be regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

[0028] In addition to salt forms, the present invention providescompounds which are in a prodrug form. Prodrugs of the compoundsdescribed herein are those compounds that readily undergo chemicalchanges under physiological conditions to provide the compounds of thepresent invention. Additionally, prodrugs can be converted to thecompounds of the present invention by chemical or biochemical methods inan ex vivo environment. For example, prodrugs can be slowly converted tothe compounds of the present invention when placed in a transdermalpatch reservoir with a suitable enzyme or chemical reagent.

[0029] Certain compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms are equivalent to unsolvated forms and areintended to be encompassed within the scope of the present invention.Certain compounds of the present invention may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated by the present invention and areintended to be within the scope of the present invention.

[0030] Certain compounds of the present invention possess asymmetriccarbon atoms (optical centers) or double bonds; the racemates,diastereomers, geometric isomers and individual isomers are all intendedto be encompassed within the scope of the present invention.

[0031] The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

[0032] General:

[0033] A new class of compounds that interact with PPARγ has now beendiscovered. Depending on the biological environment (e.g., cell type,pathological condition of the host, etc.), these compounds can activateor block the actions of PPARγ. By activating the PPARγ receptor, thecompounds will find use as therapeutic agents capable of modulatingconditions mediated by the PPARγ receptor. As noted above, example ofsuch conditions is NIDDM. Additionally, the compounds are useful for theprevention and treatment of complications of diabetes (e.g., neuropathy,retinopathy, glomerulosclerosis, and cardiovascular disorders), andtreating hyperlipidemia. Still further, the compounds are useful for themodulation of inflammatory conditions which most recently have beenfound to be controlled by PPARγ (see, Ricote, et al., Nature, 391:79-82(1998) and Jiang, et al., Nature, 391:82-86 (1998). Examples ofinflammatory conditions include rheumatoid arthritis andatherosclerosis.

[0034] Compounds that act via antagonism of PPARγ are useful fortreating obesity, hypertension, hyperlipidemia, hypercholesterolemia,hyperlipoproteinemia, and metabolic disorders.

EMBODIMENTS OF THE INVENTION

[0035] In one aspect, the present invention provides compounds which arerepresented by the formula:

[0036] In formula (I), the symbol Ar¹ represents a substituted orunsubstituted aryl group. Preferably, Ar¹ is a monocyclic or fusedbicyclic aryl group having from zero to four heteroatoms as ringmembers. More preferably, Ar¹ is a monocyclic or fused bicyclic arylgroup comprising two fused six-membered rings, two fused five-memberedrings, or a six-member ring having a fused five-membered ring.heteroaryl group containing from 1 to 3 nitrogen atoms in the ring orrings. Particularly preferred embodiments are those in which Ar¹ isphenyl, naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-pyrimidyl, isoquinolinyl, benzothiazolyl, benzoxazolyl,and benzimidazolyl, with the proviso that when Ar¹ is substituted orunsubstituted 2-benzothiazolyl, then X is —S(O)_(k)— wherein thesubscript k is 0, 1 or 2. As noted above, Ar¹ can be both unsubstitutedand substituted. In preferred embodiments, Ar¹ is substituted with from0 to 3 substituents selected from halogen, —OCF₃, —OH, —O—(C₁-C₆)alkyl,—CF₃, (C₁-C₆)alkyl, or —NO₂. In one group of preferred embodiments, Ar¹is a monocyclic heteroaryl group containing 1 to 2 nitrogen atoms in thering and being monosubstituted by halogen, —OCF₃ or —CF₃. In anothergroup of preferred embodiments, Ar¹ is a phenyl or naphthyl group havingfrom 1 to 3 substituents selected from halogen, cyano, nitro,(C₁-C₈)alkyl or (C₁-C₈)alkoxy.

[0037] The letter X represents a divalent linkage selected fromsubstituted or unsubstituted (C₁-C₆)alkylene, substituted orunsubstituted (C₁-C₆)alkylenoxy, substituted or unsubstituted(C₁-C₆)alkylenamino, substituted or unsubstituted(C₁-C₆)alkylene-S(O)_(k), —O—, —C(O)—, —N(R¹¹)—, —N(R¹¹)C(O)—,—S(O)_(k)— and a single bond, in which R¹¹ is a member selected fromhydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and aryl(C₁-C₄)alkyl and thesubscript k is an integer of from 0 to 2. In preferred embodiments, Xrepresents —O—, —C(O)—, substituted or unsubstituted (C₁-C₆)alkylene,—N(R¹¹)—, or —S(O)_(k)—. Most preferably, X represents —O—, —CH₂—,—CH(CH₃)—, —CH(CH₂CH₃)—, —CH(isopropyl)—, —CH(CN)—, —C(O)—, —N(R¹¹)—, or—S(O)_(k)—. Still further preferred are those embodiments in which Xrepresents —O—, —CH₂—, —CH(CH₃)—, —C(O)—, —N(R¹¹)—, or —S(O)_(k)—,wherein R¹¹ is hydrogen, methyl, ethyl, propyl and isopropyl.

[0038] The letter Y, in the above formula represents a divalent linkageselected from substituted or unsubstituted (C₁-C₆)alkylene, —O—, —C(O)—,—N(R¹²)—S(O)_(m)—, —N(R¹²)—S(O)_(m)—N(R¹³)—, —N(R¹²)C(O)—, —S(O)_(n)—, asingle bond, and combinations thereof, in which R¹² and R¹³ are membersindependently selected from hydrogen, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₂-C₈)heteroalkyl andsubstituted or unsubstituted aryl(C₁-C₄)alkyl; and the subscripts m andn are independently integers of from 0 to 2. In preferred embodiments, Yrepresents —N(R¹²)—S(O)₂— or —N(R¹²)—C(O)—. More preferably, Yrepresents —N(R¹²)—S(O)₂— in which R¹² is hydrogen or substituted orunsubstituted (C₁-C₈)alkyl. Most preferably, Y represents —NH—S(O)₂—.Additionally, the linkages provided herein (represented by X and Y) canbe in either orientation. More particularly, for example, the nitrogenatom of —N(R¹²)—S(O)₂— can be attached to either the central benzenering or to the R² group.

[0039] The symbol R¹ represents a member selected from hydrogen,halogen, cyano, nitro, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, —CO₂R¹⁴,—C(O)NR¹⁵R¹⁶, —C(O)R¹⁴, —S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—OR¹⁷,—O—C(O)—R¹⁷, —O—C(O)—NR¹⁵R¹⁶, —N(R¹⁴)—C(O)—NR¹⁵R¹⁶, —N(R¹⁴)—C(O)—R¹⁷ and—N(R¹⁴)—C(O)—OR¹⁷, in which R¹⁴ is a member selected from hydrogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from hydrogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, aryl, and aryl(C₁-C₄)alkyl, or taken together withthe nitrogen to which each is attached form a 5-, 6- or 7-membered ring;and R¹⁷ is a member selected from hydrogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl. In each of thedescriptions of, for example, alkyl, alkoxy and heteroalkyl, the groupscan be substituted or unsubstituted. Preferably, when substituted thesubstituents are halogen (e.g., —CF₃, —OCF₃). In preferred embodiments,R¹ represents hydrogen, halogen, cyano, (C₁-C₈)alkyl, (C₁-C₈)alkoxy,—CO₂R¹⁴ and —C(O)NR¹⁵R¹⁶. More preferably, R¹ represents hydrogen,halogen, cyano, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, —CO₂R¹⁴ and —C(O)NR¹⁵R¹⁶ inwhich R¹⁴ is (C₁-C₈)alkyl, and R¹⁵ and R¹⁶ are independently hydrogen or(C₁-C₈)alkyl, or taken together with the nitrogen to which each isattached form a 5- or 6-membered ring. Other preferred R¹ groups arediscussed below with reference to groupings of compounds wherein Ar¹ isphenyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, benzoxazolyl,benzothiazolyl and benzimidazolyl.

[0040] The symbol R² represents a substituted or unsubstituted arylgroup. Preferably, R² represents a phenyl, naphthyl, pyridazinyl orpyridyl group. More preferably, R² is a phenyl, naphthyl, pyridazinyl orpyridyl group substituted with from 0-3 substituents selected fromhalogen, —OCF₃, —OH, —O(C₁-C₈)alkyl, —CN, —CF₃, —C(O)—(C₁-C₈)alkyl,—(C₁-C₈)alkyl and —NH₂. While certain preferred substituents have beenprovided (e.g., —OCF₃ and —CF₃), the terms alkyl and alkoxy are alsomeant to include substituted versions thereof, preferablyhalosubstituted versions including those specifically noted.

[0041] The symbol R³ represents a halogen, cyano, nitro or a substitutedor unsubstituted (C₁-C₈)alkoxy group, preferably a halogen, cyano or(C₁-C₄)alkoxy group. Most preferably, halogen, methoxy ortrifluoromethoxy.

[0042] A number of preferred embodiments are provided herein. Forexample, in one preferred embodiment, X is a divalent linkage selectedfrom —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)— and —S—; and Y is—N(R¹²)—S(O)₂—, wherein R¹² is a member selected from hydrogen and(C₁-C₈)alkyl. In another preferred embodiment, X is a divalent linkageselected from —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)— and —S—; Y is—N(R¹²)—S(O)₂—, wherein R¹² is a member selected from hydrogen and(C₁-C₈)alkyl; and R² is a substituted or unsubstituted aryl selectedfrom phenyl, pyridyl, naphthyl and pyridazinyl. In yet another preferredembodiment, X is a divalent linkage selected from —CH₂—, —CH(CH₃)—, —O—,—C(O)—, —N(R¹¹)— and —S—; Y is —N(R¹²)—S(O)₂—, wherein R¹² is a memberselected from hydrogen and (C₁-C₈)alkyl; R² is a substituted orunsubstituted aryl selected from phenyl, pyridyl, naphthyl andpyridazinyl; and Ar¹ is a substituted or unsubstituted aryl selectedfrom pyridyl, phenyl, naphthyl, quinolinyl, isoquinolinyl, benzoxazolyl,benzothiazolyl, and benzimidazolyl.

[0043] One of skill in the art will understand that a number ofstructural isomers are represented by formula I. In one group ofembodiments, the isomers are those in which the groups on the phenylring occupy positions that are not contiguous. In other embodiments, thecompounds are those having the structural orientations represented bythe formulae:

[0044] Still further preferred are those compounds having the structuralorientation represented by formula Ia or Ib. Still other preferredcompounds, are those of formula Ia or Ib in which the positions of R¹and R³ are switched (or reversed).

[0045] Yet other preferred compounds are those in which Ar¹—X— and —Y—R²occupy positions ortho to one another (exemplified by Ij).

[0046] Still another group of preferred compounds are represented by theformula:

[0047] Ar¹ is substituted or unsubstituted phenyl

[0048] In one group of particularly preferred embodiments, Ar¹ is asubstituted or unsubstituted phenyl group. Further preferred are thoseembodiments in which the compound is represented by any of formulae Iathrough Ij. Still further preferred are those embodiments in which X is—O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selected from hydrogen,halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴,—CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is aphenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂; and R³ is selected from halogen, methoxy and trifluoromethoxy.

[0049] Other particularly preferred embodiments wherein Ar¹ issubstituted or unsubstituted phenyl, are those that are represented byeither of formulae Ii or Ij. In this group of embodiments, X is adivalent linkage selected from —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)—and —S—, wherein R¹¹ is a member selected from hydrogen and(C₁-C₈)alkyl; Y is a divalent linkage selected from —N(R¹²)—S(O)₂—,wherein R¹² is a member selected from hydrogen and (C₁-C₈)alkyl; R¹ is amember selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and —N(R¹⁴)—C(O)—R¹⁷,wherein R¹⁴ is a member selected from hydrogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶ are membersindependently selected from hydrogen, (C₁-C₈)alkyl and(C₂-C₈)heteroalkyl, or taken together with the nitrogen to which each isattached form a 5-, 6- or 7-membered ring; R¹⁷ is a member selected fromhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is aninteger of from 0 to 2; the subscript q is 2; R² is a substituted orunsubstituted phenyl; and R³ is a halogen or (C₁-C₈)alkoxy.

[0050] In further preferred embodiments, X is —O—, —NH— or —S—; Y is—NH—SO₂—; R¹ is a member selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R ⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0to 3 substitutents selected from halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl,—C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂; and R³ is selectedfrom halogen, methoxy and trifluoromethoxy.

[0051] In still further preferred embodiments, Ar¹ is a phenyl grouphaving from 1 to 3 substituents selected from halogen, —OCF₃, —OH,—O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl and —NO₂; R¹ is a member selectedfrom halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² isa phenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂, more preferably 1 to 3 substituents selected from halogen,—OCF₃ and —CF₃; and R³ is selected from halogen, methoxy andtrifluoromethoxy. Yet further preferred embodiments are those in whichR¹ and R³ are each independently a halogen, and R² is a phenyl grouphaving from 1 to 3 substitutents selected from halogen, —OCF₃, and —CF₃.

[0052] Ar¹ is substituted or unsubstituted phyridyl

[0053] In one group of particularly preferred embodiments, Ar¹ is asubstituted or unsubstituted pyridyl group. Further preferred are thoseembodiments in which the compound is represented by any of formulae Iathrough Ij. Still further preferred are those embodiments in which X is—O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selected from hydrogen,halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴,—CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is aphenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂; and R³ is selected from halogen, methoxy and trifluoromethoxy.

[0054] Other particularly preferred embodiments wherein Ar¹ issubstituted or unsubstituted pyridyl, are those that are represented byeither of formulae Ii or Ij. In this group of embodiments, X is adivalent linkage selected from —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)—and —S—, wherein R¹¹ is a member selected from hydrogen and(C₁-C₈)alkyl; Y is a divalent linkage selected from —N(R¹²)—S(O)₂—,wherein R¹² is a member selected from hydrogen and (C₁-C₈)alkyl; R¹ is amember selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and —N(R¹⁴)—C(O)—R¹⁷,wherein R¹⁴ is a member selected from hydrogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶ are membersindependently selected from hydrogen, (C₁-C₈)alkyl and(C₂-C₈)heteroalkyl, or taken together with the nitrogen to which each isattached form a 5-, 6- or 7-membered ring; R¹⁷ is a member selected fromhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is aninteger of from 0 to 2; the subscript q is 2; R² is a substituted orunsubstituted phenyl; and R³ is a halogen or (C₁-C₈)alkoxy.

[0055] In further preferred embodiments, X is —O—, —NH— or —S—; Y is—NH—SO₂—; R¹ is a member selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0to 3 substitutents selected from halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl,—C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂; and R³ is selectedfrom halogen, methoxy and trifluoromethoxy.

[0056] In still further preferred embodiments, Ar¹ is a pyridyl grouphaving from 0 to 3 substituents selected from halogen, —OCF₃, —OH,—O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl and —NO₂; R¹ is a member selectedfrom halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² isa phenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂, more preferably 1 to 3 substituents selected from halogen,—OCF₃ and —CF₃; and R³ is selected from halogen, methoxy andtrifluoromethoxy. Yet further preferred embodiments are those in whichR¹ and R³ are each independently a halogen, and R² is a phenyl grouphaving from 1 to 3 substitutents selected from halogen, —OCF₃, and —CF₃.Most preferably, Ar¹ is a 3-pyridyl group having preferred substituentsas indicated above.

[0057] In still other particularly preferred embodiments, the compoundsare represented by formula I, in which Ar¹ is a pyridyl ring having asingle substituent selected from halogen, —OCF₃ and —CF₃; X is adivalent linkage selected from the group of —O—, —C(O)—, —CH₂— andcombinations thereof; Y is a divalent linkage selected from the group of—NH—S(O)₂— and —NH—C(O)—; R¹ is selected from hydrogen, halogen, cyano,(C₁-C₈)alkyl, (C₁-C₈)alkoxy and —C(O)NR¹⁵R¹⁶ in which R¹⁵ and areselected from hydrogen, (C₁-C₈)alkyl, aryl and aryl(C₁-C₄)alkyl; R² is aphenyl or pyridyl ring, optionally substituted by 0-3 groups selectedfrom halogen, (C₁-C₈)alkyl, —O—(C₁-C₈)alkyl and —CN; and R³ is halogen,cyano or (C₁-C₄)alkoxy.

[0058] Ar¹ is substituted or unsubstituted naphthyl

[0059] In one group of particularly preferred embodiments, Ar¹ is asubstituted or unsubstituted naphthyl group. Further preferred are thoseembodiments in which the compound is represented by any of formulae Iathrough Ij. Still further preferred are those embodiments in which X is—O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selected from hydrogen,halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴,—CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is aphenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂; and R³ is selected from halogen, methoxy and trifluoromethoxy.

[0060] Other particularly preferred embodiments wherein Ar¹ issubstituted or unsubstituted naphthyl, are those that are represented byeither of formulae Ii or Ij. In this group of embodiments, X is adivalent linkage selected from —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)—and —S—, wherein R¹¹ is a member selected from hydrogen and(C₁-C₈)alkyl; Y is a divalent linkage selected from —N(R¹²)—S(O)₂—,wherein R¹² is a member selected from hydrogen and (C₁-C₈)alkyl; R¹ is amember selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and —N(R¹⁴)—C(O)—R¹⁷,wherein R¹⁴ is a member selected from hydrogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶ are membersindependently selected from hydrogen, (C₁-C₈)alkyl and(C₂-C₈)heteroalkyl, or taken together with the nitrogen to which each isattached form a 5-, 6- or 7-membered ring; R¹⁷ is a member selected fromhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is aninteger of from 0 to 2; the subscript q is 2; R² is a substituted orunsubstituted phenyl; and R³ is a halogen or (C₁-C₈)alkoxy.

[0061] In further preferred embodiments, X is —O—, —NH— or —S—; Y is—NH—SO₂—; R¹ is a member selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0to 3 substitutents selected from halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl,—C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂; and R³ is selectedfrom halogen, methoxy and trifluoromethoxy.

[0062] In still further preferred embodiments, Ar¹ is a naphthyl grouphaving from 0 to 3 substituents selected from halogen, —OCF₃, —OH,—O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl and —NO₂; R¹ is a member selectedfrom halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² isa phenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂, more preferably 1 to 3 substituents selected from halogen,—OCF₃ and —CF₃; and R³ is selected from halogen, methoxy andtrifluoromethoxy. Yet further preferred embodiments are those in whichR¹ and R³ are each independently a halogen, and R² is a phenyl grouphaving from 1 to 3 substitutents selected from halogen, —OCF₃, and —CF₃.

[0063] Ar¹ is substituted or unsubstituted benzothiazolyl

[0064] In another group of particularly preferred embodiments, Ar¹ is asubstituted or unsubstituted benzothiazolyl group, with the proviso thatwhen Ar¹ is substituted or unsubstituted 2-benzothiazolyl, then X is—S(O)_(k)—. Further preferred are those embodiments in which thecompound is represented by any of formulae Ia through Ij. Still furtherpreferred are those embodiments in which X is —O—, —NH— or —S—; Y is—NH—SO₂—; R¹ is a member selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0to 3 substitutents selected from halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl,—C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂; and R³ is selectedfrom halogen, methoxy and trifluoromethoxy.

[0065] Other particularly preferred embodiments wherein Ar¹ issubstituted or unsubstituted benzothiazolyl, are those that arerepresented by either of formulae Ii or Ij. In this group ofembodiments, X is a divalent linkage selected from —CH₂—, —CH(CH₃)—,—O—, —C(O)—, —N(R¹¹)— and —S—, wherein R¹¹ is a member selected fromhydrogen and (C₁-C₈)alkyl; Y is a divalent linkage selected from—N(R¹²)—S(O)₂—, wherein R¹² is a member selected from hydrogen and(C₁-C₈)alkyl; R¹ is a member selected from hydrogen, halogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴,—C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and—N(R¹⁴)—C(O)—R¹⁷, wherein R¹⁴ is a member selected from hydrogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from hydrogen, (C₁-C₈)alkyl and(C₂-C₈)heteroalkyl, or taken together with the nitrogen to which each isattached form a 5-, 6- or 7-membered ring; R¹⁷ is a member selected fromhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is aninteger of from 0 to 2; the subscript q is 2; R² is a substituted orunsubstituted phenyl; and R³ is a halogen or (C₁-C₈)alkoxy.

[0066] In further preferred embodiments, X is —O—, —NH— or —S—; Y is—NH—SO₂—; R¹ is a member selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0to 3 substitutents selected from halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl,—C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂; and R³ is selectedfrom halogen, methoxy and trifluoromethoxy.

[0067] In still further preferred embodiments, Ar¹ is a benzothiazolylgroup having from 1 to 3 substituents selected from halogen, —OCF₃, —OH,—O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl and —NO₂; R¹ is selected fromhalogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² is aphenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂, more preferably 1 to 3 substituents selected from halogen,—OCF₃ and —CF₃; and R³ is selected from halogen, methoxy andtrifluoromethoxy. Yet further preferred embodiments are those in whichR¹ and R³ are each independently a halogen, and R² is a phenyl grouphaving from 1 to 3 substitutents selected from halogen, —OCF₃, and —CF₃.In particularly preferred embodiments, the benzothiazolyl group is a2-benzothiazolyl group.

[0068] Ar¹ is substituted or unsubstituted benzoxazolyl

[0069] In another group of particularly preferred embodiments, Ar¹ is asubstituted or unsubstituted benzoxazolyl group. Further preferred arethose embodiments in which the compound is represented by any offormulae Ia through Ij.

[0070] Still further preferred are those embodiments in which X is —O—,—NH— or —S—; Y is —NH—SO₂—; R¹ is a member selected from hydrogen,halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴,—CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is aphenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂; and R³ is selected from halogen, methoxy and trifluoromethoxy.

[0071] Other particularly preferred embodiments wherein Ar¹ issubstituted or unsubstituted benzoxazolyl, are those that arerepresented by either of formulae Ii or Ij. In this group ofembodiments, X is a divalent linkage selected from —CH₂—, —CH(CH₃)—,—O—, —C(O)—, —N(R¹¹)— and —S—, wherein R¹¹ is a member selected fromhydrogen and (C₁-C₈)alkyl; Y is a divalent linkage selected from—N(R¹²)—S(O)₂—, wherein R¹² is a member selected from hydrogen and(C₁-C₈)alkyl; R¹ is a member selected from hydrogen, halogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴,—C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and—N(R¹⁴)—C(O)—R¹⁷, wherein R¹⁴ is a member selected from hydrogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from hydrogen, (C₁-C₈)alkyl and(C₂-C₈)heteroalkyl, or taken together with the nitrogen to which each isattached form a 5-, 6- or 7-membered ring; R¹⁷ is a member selected fromhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is aninteger of from 0 to 2; the subscript q is 2; R² is a substituted orunsubstituted phenyl; and R³ is a halogen or (C₁-C₈)alkoxy.

[0072] In further preferred embodiments, X is —O—, —NH— or —S—; Y is—NH—SO₂—;

[0073] R¹ is a member selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0to 3 substitutents selected from halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl,—C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂; and R³ is selectedfrom halogen, methoxy and trifluoromethoxy.

[0074] In still further preferred embodiments, Ar¹ is a benzoxazolylgroup having from 0 to 3 substituents selected from halogen, —OCF₃, —OH,—O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl and —NO₂; R¹ is selected fromhalogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² is aphenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂, more preferably 1 to 3 substituents selected from halogen,—OCF₃ and —CF₃; and R³ is selected from halogen, methoxy andtrifluoromethoxy. Yet further preferred embodiments are those in whichR¹ and R³ are each independently a halogen, and R² is a phenyl grouphaving from 1 to 3 substitutents selected from halogen, —OCF₃, and —CF₃.In particularly preferred embodiments, the benzoxazolyl group is a2-benzoxazolyl group.

[0075] Ar¹ is substituted or unsubstituted benzimidazolyl

[0076] In another group of particularly preferred embodiments, Ar¹ is asubstituted or unsubstituted benzimidazolyl group. Further preferred arethose embodiments in which the compound is represented by any offormulae Ia through Ij. Still further preferred are those embodiments inwhich X is —O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selected fromhydrogen, halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy,—C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R²is a phenyl group having from 0 to 3 substitutents selected fromhalogen, —OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃,(C₁-C₈)alkyl and —NH₂; and R³ is selected from halogen, methoxy andtrifluoromethoxy.

[0077] Other particularly preferred embodiments wherein Ar¹ issubstituted or unsubstituted benzimidazolyl, are those that arerepresented by either of formulae Ii or Ij. In this group ofembodiments, X is a divalent linkage selected from —CH₂—, —CH(CH₃)—,—O—, —C(O)—, —N(R¹¹)— and —S—, wherein R¹¹ is a member selected fromhydrogen and (C₁-C₈)alkyl; Y is a divalent linkage selected from—N(R¹²)—S(O)₂—, wherein R¹² is a member selected from hydrogen and(C₁-C₈)alkyl; R¹ is a member selected from hydrogen, halogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴,—C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and—N(R¹⁴)—C(O)—R¹⁷, wherein R¹⁴ is a member selected from hydrogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from hydrogen, (C₁-C₈)alkyl and(C₂-C₈)heteroalkyl, or taken together with the nitrogen to which each isattached form a 5-, 6- or 7-membered ring; R¹⁷ is a member selected fromhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is aninteger of from 0 to 2; the subscript q is 2; R² is a substituted orunsubstituted phenyl; and R³ is a halogen or (C₁-C₈)alkoxy.

[0078] In further preferred embodiments, X is —O—, —NH— or —S—; Y is—NH—SO₂—; R¹ is a member selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0to 3 substitutents selected from halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl,—C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂; and R³ is selectedfrom halogen, methoxy and trifluoromethoxy.

[0079] In still further preferred embodiments, Ar¹ is a benzimidazolylgroup having from 0 to 3 substituents selected from halogen, —OCF₃, —OH,—O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl and —NO₂; R¹ is selected fromhalogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² is aphenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂, more preferably 1 to 3 substituents selected from halogen,—OCF₃ and —CF₃; and R³ is selected from halogen, methoxy andtrifluoromethoxy. Yet further preferred embodiments are those in whichR¹ and R³ are each independently a halogen, and R² is a phenyl grouphaving from 1 to 3 substitutents selected from halogen, —OCF₃, and —CF₃.In particularly preferred embodiments, the benzimidazolyl group is a2-benzimidazolyl group.

[0080] Ar¹ is substituted or unsubstituted quinolinyl or isoquinolinyl

[0081] In another group of particularly preferred embodiments, Ar¹ is asubstituted or unsubstituted isoquinolinyl group. Further preferred arethose embodiments in which the compound is represented by any offormulae Ia through Ij. Still further preferred are those embodiments inwhich X is —O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selected fromhydrogen, halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy,—C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R²is a phenyl group having from 0 to 3 substitutents selected fromhalogen, —OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃,(C₁-C₈)alkyl and —NH₂; and R³ is selected from halogen, methoxy andtrifluoromethoxy.

[0082] Other particularly preferred embodiments wherein Ar¹ issubstituted or unsubstituted isoquinolinyl, are those that arerepresented by either of formulae Ii or Ij. In this group ofembodiments, X is a divalent linkage selected from —CH₂—, —CH(CH₃)—,—O—, —C(O)—, —N(R¹¹)— and —S—, wherein R¹¹ is a member selected fromhydrogen and (C₁-C₈)alkyl; Y is a divalent linkage selected from—N(R¹²)—S(O)₂—, wherein R¹² is a member selected from hydrogen and(C₁-C₈)alkyl; R¹ is a member selected from hydrogen, halogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴,—C(O)NR¹⁵R¹⁶, —S(O)_(p)—R⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and—N(R¹⁴)—C(O)—R¹⁷, wherein R¹⁴ is a member selected from hydrogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from hydrogen, (C₁-C₈)alkyl and(C₂-C₈)heteroalkyl, or taken together with the nitrogen to which each isattached form a 5-, 6- or 7-membered ring; R¹⁷ is a member selected fromhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is aninteger of from 0 to 2; the subscript q is 2; R² is a substituted orunsubstituted phenyl; and R³ is a halogen or (C₁-C₈)alkoxy.

[0083] In further preferred embodiments, X is —O—, —NH— or —S—; Y is—NH—SO₂—; R¹ is a member selected from hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴ and —S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0to 3 substitutents selected from halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl,—C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂; and R³ is selectedfrom halogen, methoxy and trifluoromethoxy.

[0084] In still further preferred embodiments, Ar¹ is an isoquinolinylgroup having from 0 to 3 substituents selected from halogen, —OCF₃, —OH,—O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl and —NO₂; R¹ is selected fromhalogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² is aphenyl group having from 0 to 3 substitutents selected from halogen,—OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyland —NH₂, more preferably 1 to 3 substituents selected from halogen,—OCF₃ and —CF₃; and R³ is selected from halogen, methoxy andtrifluoromethoxy. Yet further preferred embodiments are those in whichR¹ and R³ are each independently a halogen, and R² is a phenyl grouphaving from 1 to 3 substitutents selected from halogen, —OCF₃, and —CF₃.In particularly preferred embodiments, the isoquinolinyl group isselected from 3-isoquinolinyl and 4-isoquinolinyl groups.

[0085] In another aspect, the present invention provides pharmaceuticalcompositions comprising at least one of the above compounds in admixturewith a pharmaceutically acceptable excipient.

[0086] In yet another aspect, the present invention provides methods formodulating conditions mediated by PPARγ in a host. More particularly,the conditions are selected from non-insulin-dependent diabetesmellitus, obesity, conditions associated with abnormal plasma levels oflipoproteins or triglycerides, and inflammatory conditions such as, forexample, rheumatoid arthritis and atherosclerosis.

[0087] Preparation of the Compounds The compounds of the presentinvention can be prepared using standard synthetic methods. Forexemplary purposes, Scheme 1 illustrates methods for the preparation ofcompounds of structural formula (Ia). One of skill in the art willunderstand that similar methods can be used for the synthesis ofcompounds in the other structural classes.

[0088] As shown in Scheme 1, compounds of the present invention can beprepared beginning with commercially available2-chloro-5-nitrobenzonitrile (i). Treatment of J with a phenol,thiophenol, or optionally protected aniline in the presence of base andheat provides the adduct (ii). Reduction of the nitro group in ii with,for example, H₂ in the presence of Raney nickel catalyst provides ananiline derivative (iii). Sulfonylation of iii with an appropriatearylsulfonyl halide (Ar¹ 50₂C₁) in the presence of base (typically atertiary amine) provides a target compound (iv). Compound iii can alsobe converted to a related compound of formula (vi) in which theorientation of the sulfonamide linkage is reversed. Thus, conversion ofthe aniline iii to the benzenesulfonyl chloride v can be accomplishedusing methods described in Hoffman, Organic Syntheses Collective VolumeVII, p. 508-511. Subsequent treatment of v with an appropriate anilineprovides the target compound vi.

[0089] Other compounds of the present invention can be preparedbeginning with, for example, 3,4-difluoronitrobenzene,3-chloro-4-fluoronitrobenzene, 2-chloro-5-nitroanisole,3-bromo-4-fluoronitrobenzene and the like.

[0090] Analysis of the Compounds

[0091] The compounds of the present invention can be evaluated formodulation of the PPARγ receptor using assays such as those described inJiang, et al., Nature 391:82-86 (1998), Ricote, et al., Nature 391:79-82(1998) and Lehmann, et al., J. Biol. Chem. 270(12): 12953-12956 (1995).Alternatively, the compounds can be evaluated for their ability todisplace radiolabeled BRL 49653 from a PPARγ-GST fusion protein asfollows:

[0092] Materials:

[0093] PPARγ-GST fusion protein (prepared according to standardprocedures), [3H]-BRL 49653 having 50 Ci/mmol specific activity,Polyfiltronics Unifilter 350 filtration plate and glutathione-Sepharose®beads (from Pharmacia: washed twice with 10× binding buffer in which BSAand DTI can be left out).

[0094] Method:

[0095] Binding buffer (10 mM Tris-HCl, pH 8.0, 50 mM KCl, 10 mM DTT,0.02% BSA and 0.01% NP-40) is added in 80 microliter amounts to thewells of the filtration plate. The test compound is then added in 10microliters of DMSO. The PPARγ-GST fusion protein and radiolabeled BRLcompound are premixed in binding buffer containing 10 mM DTT and addedin 10 microliter amounts to the wells of the plate to provide finalconcentrations of 1 μg/well of PPARγ-GST fusion protein and 10 nM[³H]-BRL 49653 compound. The plate is incubated for 15 minutes.Glutathione-agarose bead is added in 50 μL of binding buffer, and theplate is vigorously shaken for one hour. The plate is washed four timeswith 200 μL/well of binding buffer (without BSA and DTT). The bottom ofthe plate is sealed and 200 μL/well of scintillation cocktail is added.The top of the plate is then sealed and the radioactivity is determined.

[0096] Formulation and Administration of the Compounds (Compositions)

[0097] The compounds of the present invention can be prepared andadministered in a wide variety of oral and parenteral dosage forms.Thus, the compounds of the present invention can be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds described herein can be administered by inhalation, forexample, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. Accordingly, the presentinvention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and either a compoundof formula (I) or a pharmaceutically acceptable salt of a compound offormula (I).

[0098] For preparing pharmaceutical compositions from the compounds ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories; and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

[0099] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

[0100] The powders and tablets preferably contain from 5% or 10% to 70%of the active compound. Suitable carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

[0101] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

[0102] Liquid form preparations include solutions, suspensions, andemulsions, for example, water or water/propylene glycol solutions. Forparenteral injection, liquid preparations can be formulated in solutionin aqueous polyethylene glycol solution.

[0103] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizers, and thickening agents as desired. Aqueoussuspensions suitable for oral use can be made by dispersing the finelydivided active component in water with viscous material, such as naturalor synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

[0104] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0105] The pharmaceutical preparation is preferably in unit dosage form.In such form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0106] The quantity of active component in a unit dose preparation maybe varied or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100mg according to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

[0107] In therapeutic use for the treatment of obesity, NIDDM, orinflammatory conditions, the compounds utilized in the pharmaceuticalmethod of the invention are administered at the initial dosage of about0.001 mg/kg to about 100 mg/kg daily. A daily dose range of about 0.1mg/kg to about 10 mg/kg is preferred. The dosages, however, may bevaried depending upon the requirements of the patient, the severity ofthe condition being treated, and the compound being employed.Determination of the proper dosage for a particular situation is withinthe skill of the practitioner. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired.

[0108] The following examples are offered by way of illustration and arenot intended to limit the scope of the invention.

EXAMPLES

[0109] Reagents and solvents used below can be obtained from commercialsources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMRspectra were recorded on a Varian Gemini 400 MHz NMR spectrometer.Significant peaks are tabulated in the order: number of protons,multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br s, broad singlet) and coupling constant(s) in Hertz.Electron Ionization (EI) mass spectra were recorded on a Hewlett Packard5989A mass spectrometer. Mass spectrometry results are reported as theratio of mass over charge, followed by the relative abundance of eachion (in parentheses). In tables, a single m/e value is reported for theM+H (or as noted M−H) ion containing the most common atomic isotopes.Isotope patterns correspond to the expected formula in all cases.Electrospray ionization (ESI) mass spectrometry analysis was conductedon a Hewlett-Packard 1100 MSD electrospray mass spectrometer using theHP1 100 HPLC for sample delivery. Normally the analyte was dissolved inmethanol at 0.1 mg/mL and 1 microliter was infused with the deliverysolvent into the mass spectrometer which scanned from 100 to 1500daltons. All compounds could be analyzed in the positive ESI mode, using1:1 acetonitrile/water with 1% acetic acid as the delivery solvent. Thecompounds provided below could also be analyzed in the negative ESImode, using 2 mM NH₄OAc in acetonitrile/water as delivery solvent.

[0110] Abbreviations: N-hydroxybenzotriazole (HOBT),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), N-methylmorpholine (NMM),: 1-hydroxy-7-azabenzotriazole (HOAT),O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).

Example 1

[0111] This example illustrates the preparation of5-nitro-2-(3-chloro-5-pyridyloxy)benzonitrile (1.1).

[0112] To a solution of 2-chloro-5-nitrobenzonitrile (18.3 g, 100 mmol)and 5-chloro 3-pyridinol (13 g, 100 mmol) in DMIF (100 mL) was addedpowdered K2C03 (13.9 g, 100 mmol). After heating at 60° C. for 12 hours,the suspension was poured into water (1 L). The resulting solid wascollected by filtration, rinsed with water and dried under vacuum toafford 27.6 g (100%) of the title compound, mp 104-107° C.

[0113]¹H NMR (400 MHz) (DMSO-d₆) δ 8.755 (d, J=2.8 Hz, 1H); 8.734 (br s,1H); 8.576 (br s, 1H); 8.542 (dd, J=9.2, 2.7 Hz, 1H); 7.689 (t, J=2.2Hz, 1H); 7.122 (d, J=9.2 Hz, 1H).

Example 2

[0114] This example illustrates the preparation of5-amino-2-(3-chloro-5-pyridyloxy)benzonitrile (2.1).

[0115] To a vigorously stirred solution of the intermediate from Example1 (6.23 g) in ethanol and THF was added a slurry of Raney Nickel (−300mg, Aldrich). The flask was filled with H₂ at atmospheric pressure andthe reduction was monitored by TLC. Starting material disappearedrapidly, to form a nitroso intermediate which gradually was converted tothe desired aniline over about 5 hours. Stirring was stopped and RaneyNickel was attracted to the magnetic stirbar. The remaining solution wasfiltered through Celite® which was then rinsed with ethanol andmethylene chloride. The combined organic portions were concentrated toprovide 5.75 g of the product aniline as an oil which was used withoutfurther purification.

[0116]¹H NMR (400 MHz) (CDCl₃) δ 8.456 (d, J=1.9 Hz, 1H); 8.3 89 (d,J=2.6 Hz, 1H); 7.38 (m, 1H); 7.03 (m, 3H); 4.06 (m 2H).

Example 3

[0117] This example illustrates the synthesis of 3.1.

[0118] To a mixture of 5-amino-2-(3-chloro-5-pyridyloxy)benzonitrilefrom Example 2 (0.457 g) in methylene chloride was added2,4-dichlorobenzenesulfonyl chloride (0.456 g, from Maybridge), followedby pyridine (150 μL). The reaction progress was monitored by TLC, andupon completion the solvent was removed under vacuum. The resultingresidue was partitioned between methylene chloride and water. Theorganic layer was drawn off and concentrated. The residue was trituratedwith ether to provide 0.447 g of the title compound as a white solid, mp154-156° C.

[0119]¹H NMR (400 MHz) (CDCl₃) δ 8.59 (s, 1H); 8.42 (s, 1H) 8.08 (d,J=8.5 Hz, 1H); 7.72(t, J=1.8, 1H); 7.605 (d, J=2.7 Hz, 1H) 7.53 (dd,J=8.5, 2 Hz, 1H); 7.48 (dd, J=9.4 Hz, 1H); 7.22 (s, 1H); 7.0 (d, J=9.0Hz, 1H). m/e (M−H) 456.

[0120] The title compound was oxidized to the corresponding pyridineN-oxide using 3-chloroperoxybenzoic acid in methylene chloride toprovide 3.2 as a white solid. m/e 470 (M+H).

Example 4

[0121] This example illustrates the synthesis of 4.1.

[0122] The title compound was prepared in a manner similar to Example 3,beginning with 1.6 g of the aniline of Example 2 and 1.6 g of4-(trifluoromethyl)benzenesulfonyl chloride (from Maybridge). The crudeproduct remaining after workup was purified by flash chromatography onsilica eluting with 10% ethyl acetate/dichloromethane and thentriturated in diethyl ether and collected as a white powder (1.04 g, 35%yield), mp 143-144° C.

Example 5

[0123] This example illustrates the synthesis of 5.1.

[0124] The title compound was prepared in a manner similar to Example 3,beginning with 397 mg of the aniline prepared as described in Example 2and 345 mg of 2-chloropyridyl-5-sulfonyl chloride (prepared according toHoffman, R. V., Org Syn. Coll. Vol. VII., p. 508-511). The crude productremaining after workup was purified by flash chromatography on silicaeluting with 15% ethyl acetate/dichloromethane. The resulting solid wasrecrystalized from dichloromethane to provide the title compound (270mg, 40%) as a white solid, m/e 419 (M−H).

Example 6

[0125] This example illustrates the synthesis of 6.1.

[0126] The title compound was prepared in a manner similar to Example 3,beginning with 400 mg of the aniline prepared as described in Example 2and 349 mg of 3-pyridylsulfonyl chloride (prepared using methods similarto those described in J. Med. Chem. 40:1149 (1997)). The crude productremaining after workup was purified by flash chromatography on silicaeluting with 1% ethanol/dichloromethane. The resulting solid wasrecrystalized from dichloromethane/diethyl ether and collected as awhite solid (121 mg, 19%), mp 161-2° C.

[0127] In a similar manner, 6.2 was prepared from aniline 2.1 and5-trifluoromethyl-2-pyridinesulfonyl chloride, mp 174-176° C.

Example 7

[0128] This example illustrates the preparation of 7.1.

[0129] A round-bottomed flask was charged with the aniline preparedaccording to Example 2 (229 mg, 0.94 minol), 4-acetylbenzenesulfonylchloride (205 mg, 0.94 mmol, prepared according to Hoffman, R. V., Org.Syn. Coll. Vol. VII, p. 508-511), pyridine (75 mg, 0.94 mmol, AldrichChemical Co.), and a catalytic amount of DMAP (Aldrich Chemical Co.).Five mL of dichloromethane were added and the reaction was stirred atroom temperature for eight hours. The reaction was then diluted with 25mL of dichloromethane and washed successively with 10 mL of 1N HCl andbrine. The organic portion was dried over MgSO₄ and passed through aplug of silica gel to remove baseline impurities. The resulting solidwas triturated in hexanes to provide 362 mg (90%) of the title compoundas a white solid.

[0130]¹H NMR (400 MHz) (d₆-DMSO) δ 10.81 (1H, s); 8.52 (1H, d, J=1.8Hz); 8.43 (1H, d, J=2.3 Hz); 8.11 (2H, dd, J=6.8 Hz, 2.0 Hz); 7.90 (2H,dd, J=6.8 Hz, 2.0 Hz); 7.85 (1H, dd, J=4.4 Hz, 2.2 Hz); 7.53 (1H, d,J=2.7 Hz); 7.35 (1H, dd, J=9.1 Hz, 2.8 Hz); 7.35 (1H, d, J=9.1 Hz); 2.61(3H, s). MS ESI m/e: 425.8 (M−H).

[0131] The compounds provided in Table 1 were prepared using the methodsdescribed in Examples 1-7. TABLE 1

Ra Rb Rc Rd mp (° C.) 7.2 Cl H Cl CH₃ 181-182 7.3 H H OCF₃ H 118-120 7.4H H CN H 160-163 7.5 H H SO₂CH₃ H 174-175

Example 8

[0132] This example illustrates the preparation of3-fluoro-4-(3-chloro-5-pyridyloxy)nitrobenzene (8.1).

[0133] 3,4-Difluoronitrobenzene (5.0 g, 32 mmol) and5-chloro-3-pyridinol were combined using the procedure described inExample 1, to produce 8.2 g of the title compound.

[0134]¹H NMR (400 MHz) (DMSO-d₆) δ 8.562 (d, J=1.9 Hz, 1H); 8.537 (d,J=2.5 Hz, 1H); 8.384 (dd, J=10.8, 2.8 Hz, 1H); 8.117 (ddd, J=9.1, 2.7,1.5 Hz, 1H); 7.967 (t, J=2.2 Hz, 1H); 7.418 (dd, J=9.2, 8.4 Hz, 1H).

Example 9

[0135] This example illustrates the preparation of3-fluoro-4-(3-chloro-5-pyridyloxy)aniline (9.1).

[0136] Using the method of Example 2,3-fluoro-4-(3-chloro-5-pyridyloxy)nitrobenzene (8.1, 8.0 g) wasconverted to the title compound which was used directly in subsequentreactions.

[0137] MS (M+H) 239.1.

[0138]¹H NMR (400 MHz) (CDCl₃) δ 8.242 (br s, 2H); 7.142 (d, J=2.2 Hz,1H); 6.937 (t, J=8.7 Hz, 1H); 6.5 12 (dd, J=12, 2.6 Hz, 1H); 6.444 (ddd,J=8.4, 2.7, 1.4 Hz, 1H); 3.62 (br s, 2H).

Example 10

[0139] This example illustrates the preparation of 10.1.

[0140] 3-Fluoro-4-(3-chloro-5-pyridyloxy)aniline (239 mg, see Example 9)and 2,4-dichlorobenzenesulfonyl chloride (416 mg, Maybridge), werecombined in a similar manner to that described in Example 3. The crudeproduct was purified by flash chromatography on silica, eluting with 5%ethyl acetate/dichloromethane. The product fractions were concentratedand the solid was recrystallized from diethyl ether/hexanes to providethe title compound as a white solid (350 mg, 45%), mp 149-151° C.

Example 11

[0141] This example illustrates the preparation of 11.1.

[0142] 3-Fluoro-4-(3-chloro-5-pyridyloxy)aniline (310 mg, see Example 9)and 4-methylthiobenzenesulfonyl chloride (298 mg, prepared as describedin Burton, et al., J. Chem. Soc., 604-5 (1948)), were combined in amanner similar to that described in Example 3. The crude product waspurified by flash chromatography on silica, eluting with ethylacetate/hexanes/dichloromethane (1:5:4). The product fractions wereconcentrated and the solid was recrystallized from hexanes/diethyl etherto provide the title compound as a white solid (315 mg, 57%), mp130-131° C.

[0143] The title compound was oxidized with mCPBA to the correspondingsulfoxide (11.2, mp 140-144° C.). The corresponding sulfone (11.3) wasprepared using 4-(methylsulfonyl)benzenesulfonyl chloride (mp 165-168°C.).

Example 12

[0144] This example illustrates the preparation of 12.1.

[0145] The title compound was prepared in a manner similar to Example 3,beginning with 3-pyridylsulfonyl chloride (335 mg, see Example 6) and3-fluoro-4-(3-chloro-5-pyridyloxy)aniline (310 mg, see Example 9) withthe addition of a catalytic amount of 4-dimethylaminopyridine. Whenreaction was complete by TLC, the mixture was filtered to remove aminesalts. The filtrate was concentrated and the residue was purified byflash chromatography on silica, eluting with 5%methanol/dichloromethane. The product fractions were combined,concentrated, and the residue was triturated with diethyl ether toprovide the title compound as a white solid (221 mg, 32%), mp 129° C.

Example 13

[0146] This illustrates the synthesis of5-(4-acetylbenzenesulfonamido-2-fluorophenoxy)-3-chloropyridine (13.1).

[0147] This was prepared using methods outlined in Examples 10-12,starting with 238 mg (1.0 mmol) of aniline 9.1, 218 mg (1.0 mmol) of4-acetylbenzenesulfonyl chloride, 79 mg (1.0 mmol) of pyridine,catalytic DMAP, and S mL of methylene chloride. The title compound wasobtained as a white solid (269 mg, 64%).

[0148]¹H NMR (400 MHz) (d₆-DMSO) δ 10.75 (1H, d, J=4.7 Hz); 8.38 (1H,dd, J₁=4.8 Hz J₂=2.1 Hz); 8.26 (1H, dd, J₁=5.0 Hz J₂=2.4 Hz) 8.09 (2H,m); 7.91 (2H, m); 7.52 (1H, dd, J₁=4.7 Hz J₂=2.6 Hz); 7.21 (1H, dt, J₁=5Hz J₂=1.0 Hz); 7.12 (1H, dd, J₁=12.2 Hz J₂=1.0 Hz); 6.92 (1H, d, J=8.8Hz); 2.59 (3H, t, J=2.1 Hz). MS ESI m/e: 418.7 (M−H).

Example 14

[0149] This example illustrates the synthesis of3-chloro-4-(3-chloro-5-pyridyloxy)nitrobenzene (14.1).

[0150] 3-Chloro-4-fluoronitrobenzene (5.0 g, 28 mmol) and5-chloro-3-pyridinol were combined using the procedure described inExample 1, to produce 7.9 g of the title compound.

[0151]¹H NMR (400 MHz) (DMSO-d₆) δ 8.571 (d, J=2.0 Hz, 1H); 8.509 (d,J=2.4 Hz, 1H); 8.499 (d, J=2.7 Hz, 1H); 8.208 (dd, J=9.0, 2.7 Hz, 1H);7.949 (t, J=2.3 Hz, 1H); 7.335 (d, J=9.1 Hz, 1H).

Example 15

[0152] This example illustrates the preparation of3-chloro-4-(3-chloro-5-pyridyloxy)aniline (15.1).

[0153] Using the method of Example 2,3-chloro-4-(3-chloro-5-pyridyloxy)nitrobenzene (7.6 g) was converted tothe title compound (7.2 g) and which was used directly in subsequentreactions.

[0154]¹H NMR (400 MHz) (CDCl₃) δ 8.244 (br s, 1H); 8.211 (br s, 1H);7.096 (br 5, 1H); 6.929 (d, J=8.6 Hz, 1H); 6.785 (d, J=2.6 Hz, 1H);6.592 (dd, J=8.6, 2.6 Hz, 1H); 3.577 (br s, 2H). MS (M+H) 255.1.

Example 16

[0155] This example illustrates the preparation of 16.1.

[0156] 3-Chloro-4-(3-chloro-5-pyridyloxy)aniline (410 mg, 15.1) and2,4-dichlorobenzenesulfonyl chloride (390 mg, Maybridge), were combinedin a similar manner to that described in Example 3. The crude productwas purified by flash chromatography on silica, eluting with 5% ethylacetate/dichloromethane. The product fractions were concentrated and theresidue was triturated in hexanes to provide the title compound as awhite solid (538 mg, 73%), mp 128-130° C.

[0157]¹H NMR (400 MHz) (DMSO) δ 8.40 (d, J=1.8 Hz, 1H); 8.24 (d, J=2.4Hz, 1H); 8.06 (d, J=8.5 Hz, 1H); 7.90 (d, J=2.0 Hz, 1H); 7.65 (dd, J=2,8.5 Hz, 1H); 7.48 (t, J=2.2, 1H); 7.28 (d, J=2.5 Hz, 1H); 7.21 (d,J=8.84 Hz, 1H); 7.10 (dd, J=2.5, 7.1, 1H). MS m/e 465 (M+1).

[0158] Compound 16.1 was oxidized with 3-chloroperoxybenzoic acid toproduce the corresponding pyridine N-oxide, 16.2, as a white solid aftertrituration in diethyl ether, mp 205-207° C.

Example 17

[0159] This example illustrates the preparation of 17.1.

[0160] 3-Chloro-4-(3-chloro-5-pyridyloxy)aniline (309 mg, 15.1) and4-methylthiobenzenesulfonyl chloride (223 mg, prepared as described inBurton, et al., .1. Chem. Soc., 604-5 (1948)), were combined in a mannersimilar to that described in Example 3. The crude product was purifiedby flash chromatography on silica, eluting with ethylacetate/hexanes/dichloromethane (1:5:4). The product fractions wereconcentrated and the residue obtained was triturated in hexanes toprovide the title compound as a white solid (200 mg, 37%), mp 96-98° C.

[0161] Oxidation of 17.1 to sulfoxide 17.2

[0162] Compound 17.1 was oxidized to the corresponding sulfoxide usingOxidation to sulfoxide potassium peroxymonosulfate in methanol andacetone. The reaction was monitored by TLC. After the reaction wascomplete, the mixture was filtered and the filtrate was washed withwater, dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on silica, eluting with 50% to 100% ethylacetate/dichloromethane. Solvent was removed from the product fractions,and the residue was triturated in hexanes. The white solid product wascollected by filtration to provide 121 mg of 17.2 (63%), mp 127-128° C.

Example 18

[0163] This example illustrates the preparation of 18.1.

[0164] The title compound was prepared in a manner similar to Example 3,beginning with 3-pyridylsulfonyl chloride (335 mg, see Example 6) and3-chloro-4-(3-chloro-5-pyridyloxy)aniline (411 mg, 15.1) with theaddition of a catalytic amount of 4-dimethylaminopyridine. When thereaction was completed by TLC, the mixture was filtered to remove aminesalts. The filtrate was concentrated and the residue was purified byflash chromatography on silica, eluting with 5%methanol/dichloromethane. The product fractions were combined,concentrated, and the residue was triturated dichloromethane to providethe title compound as a white solid (149 mg, 22%), mp 164-165° C.

[0165] In a similar manner, 18.2 (mp 174-175° C.) was prepared fromaniline 15.1 and 5-trifluoromethyl-2-pyridinesulfonyl chloride.

[0166] The compounds provided in Table 2 were prepared usingcommercially available intermediates and/or using the intermediates andmethods described in the examples above. TABLE 2

Ra Rb Rc Rd mp (° C.) or m/e 18.3 H H CF₃ H 172-174° C. 18.4 Cl H CF₃ H111-113° C. 18.5 H H COCH₃ H 434.7 18.6 H Cl Cl H 460.9

Example 19

[0167] This example illustrates the preparation of3-bromo-4-(3-chloro-5-pyridyloxy)nitrobenzene (19.1).

[0168] 3-Bromo-4-fluoronitrobenzene (available from Reidel) and5-chloro-3-pyridinol were combined using the procedure described inExample 1, to produce the title compound.

[0169]¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (d, J=2.6 Hz, 1H), 8.57 (d, J=2.2Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.24 (dd, J=9.3, 2.6 Hz, 1H), 7.94 (dd,J=2.2 Hz, 1H), 7.3 (d, J=9.0 Hz, 2H). MS (EI): m/z 333 (25, M+H), 332(15, M+H), 331 (100, M+H), 330 (10, M+H), 329 (76, M+H).

Example 20

[0170] This example illustrates the preparation of3-bromo-4-(3-chloro-5-pyridyloxy)aniline (20.1).

[0171] Using the method of Example 2,3-bromo-4-(3-chloro-5-pyridyloxy)nitrobenzene (19.1) was converted tothe title compound which was used directly in subsequent reactions.

[0172]¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=2.1 Hz, 1H), 8.19 (d, J=2.5Hz, 1H), 7.28 (dd, J=2.4, 2 Hz, 1H), 7.2 (d, J=8.7 Hz, 1H), 6.9 (d,J=2.6 Hz, 1H), 6.62 (dd, J=8.7, 2.6 Hz, 1H). MS (EI): m/e 304 (5, M+H),303 (35, M+H), 302 (20, M+H), 301 (100, M+H), 300 (15, M+H), 299 (90,M+H).

[0173] The compounds provided in Table 3 were prepared using 20.1 andcommercially available intermediates and/or using the intermediates andmethods described in the examples above. TABLE 3

Ra Rb Rc Rd mp (° C.) 20.2 Cl H Cl H 114-115 20.3 H H SCH₃ H 160-16220.4 H H S(O)CH₃ H 169-171

[0174] Similarly, 20.5 was prepared from aniline 20.1 and5-trifluoromethyl-2-pyridinesulfonyl chloride, mp 202-204° C.

Example 21

[0175] This example illustrates the preparation of5-(4-nitro-2-methoxyphenoxy)-3-chloropyridine (21.1).

[0176] A round-bottomed flask was charged with 2-chloro-5-nitroanisole(1.03 g, 5.49 mmol, Avocado Chemical Co.), 5-chloro-3-pyridinol (750 mg,5.76 mmol, Aldrich Chemical Co.), cesium carbonate (1.97 g, 6.04 mmol,Aldrich Chemical Co.), and anhydrous DMF (16 mL). The mixture was heatedat 100° C. for 18 hours. The temperature was then increased to 130° C.for an additional two hours, after which the reaction was allowed tocool to room temperature. The reaction mixture was poured into 800 mL ofdistilled water, and extracted three times with 300 mL ethyl acetate.The combined extracts were dried over MgSO₄ and filtered. Solvent wasremoved from the filtrate under vacuum and the crude product waspurified by flash chromatography on silica gel (5% hexanes in CH₂Cl₂ aseluant) to provide the title compound (1.42 g, 93%) as a yellow solid.

[0177] MS ESI m/e: 281.1 (M+H).

Example 22

[0178] This example illustrates the synthesis of5-(4-amino-2-methoxyphenoxy)-3-chloropyridine (22.1).

[0179] Using the method of Example 2, the nitro compound prepared inExample 21 (1.54 g, 6.56 mmol) was converted to 1.38 g (99%) of thetitle compound as an off-white solid. The product was used withoutfurther purification (upon standing several days in air the compounddeveloped a very dark brown color).

[0180] MS ESI m/e: 251.1 (M+H).

Example 23

[0181] This example illustrates the synthesis of5-(4-(2,4-dichlorobenzenesulfonamido)-2-methoxyphenoxy)-3-chloropyridine(23.1).

[0182] A round-bottomed flask was charged with aniline 22.1 (96 mg, 0.39mmol), 2,4-dichlorobenzenesulfonyl chloride (104 mg, 0.42 mmol,Maybridge Chemical Co.), pyridine (28 mg, 0.39 mmol, Aldrich ChemicalCo.), and a catalytic amount of DMAP (Aldrich Chemical Co.). Three mL ofdichloromethane was added and the reaction mixture was stirred at roomtemperature for eight hours. The resulting mixture was then diluted with15 mL of dichloromethane and washed successively with 10 mL of 1N HCland brine. The combined organic portions were dried over MgSO₄ thenpassed through a plug of silica gel to remove baseline impurities.Solvent was removed from the filtrate and the resulting solid wastriturated in hexanes to provide the title compound (69 mg, 40%) as awhite powder.

[0183]¹H NMR (400 MHz) (d₆-DMSO) δ 10.81 (1H, s); 8.29 (1H, d, J=2.1Hz); 8.11 (1H, d, J=2.4 Hz); 8.07 (1H, d, J=8.5 Hz); 7.88 (1H, d, J=2.0Hz); 7.63 (1H, dd, J=8.7 Hz, 2.1 Hz); 7.20 (1H, dd, J=4.4 Hz, 2.1 Hz);7.07 (1H, d, J=8.7 Hz); 6.91 (1H, d, J=2.4 Hz); 6.68 (1H, dd, J=8.7 Hz,2.5 Hz); 3.65 (3H, s). MS ESI m/e: 459.0 (M+H).

Example 24

[0184] This example illustrates the synthesis of5-(4-methylsulfonylbenzenesulfonamido-2-methoxyphenoxy)-3-chloropyridine(24.1).

[0185] The title compound was prepared using the general proceduredescribed in Example 22, starting with 150 mg (0.61 mmol) of theaniline, 155 mg (0.61 mmol, Aldrich Chemical Co.) of4-methylsulfonebenzenesulfonyl chloride, 48 mg (0.61 mmol) of pyridine,catalytic DMAP, and 5 mL of methylene chloride. Following workup, thetitle compound was obtained (67 mg, 24%) as a white solid.

[0186]¹H NMR (400 MHz) (d₆-DMSO) δ 10.63 (1H, s); 8.30 (1H, d, J=2.0Hz); 8.14 (2H, m); 8.04 (1H, dd, J=8.6 Hz, 1.9 Hz); 7.27 (1H, dd, J=4.5Hz, 2.2 Hz); 7.08 (1H, d, J=8.6 Hz); 6.93 (1H, d, J=2.4 Hz); 6.70 (1H,dd, J=8.6 Hz, 2.4 Hz); 3.67 (3H, s); 3.28 (3H, s). MS ESI m/e: 467.0(M−H).

Example 25

[0187] This example illustrates the synthesis of5-(4-acetylbenzenesulfonamido-2-methoxyphenoxy)-3-chloropyridine (25.1).

[0188] The title compound was prepared using the procedure described inExample 7, starting with 82 mg (0.33 mmol) of aniline 22.1, 72 mg (0.33mmol) of 4-acetylbenzenesulfonyl chloride, 26 mg (0.33 mmol) ofpyridine, catalytic DMAP, and 2 mL of methylene chloride. The titlecompound was produced (92 mg, 65%) as a white solid.

[0189]¹H NMR (400 MHz) (d₆-DMSO) δ 10.52 (1H, s); 8.29 (1H, d, J=1.9Hz); 8.10 (3H, m); 7.92 (2H, dd, J=8.0 Hz, 2.3 Hz); 7.23 (1H, dd, J=4.5Hz, 2.4 Hz); 7.06 (1H, d, J=8.6 Hz); 6.93 (1H, dd, J=8.6 Hz, 2.4 Hz);6.70 (1H, dd, J=8.6 Hz, 2.4 Hz); 3.65 (3H, s); 2.60 (3H, s). MS ESI m/e:431.1 (M−H).

[0190] In a similar manner, 25.2 and 25.3 were prepared from aniline22.1 and the appropriate sulfonyl chloride.

Example 26

[0191] This example illustrates the preparation of5-nitro-2-(3,5-difluorophenoxy)-benzonitrile (26.1).

[0192] 2-Chloro-5-nitrobenzonitrile (4.6 g, 25 mmol) and3,5-difluorophenol were combined using the procedure described inExample 1, to produce 6.6 g of the title compound.

[0193]¹H NMR (400 MHz) (CDCl₃) δ 8.598 (d, J=2.8 Hz, 1H); 8.396 (ddd,J=9.3, 2.8, 1.2 Hz, 1H); 7.259 (d, J=0.8 Hz, 1H); 7.044 (d, J=9.6 Hz,1H); 6.821 (m, 1H); 6.722 (m, 2H).

[0194] In a similar manner, 4-chloro-3-nitrobenzonitrile (4.6 g, 25mmol) and 3,5-difluorophenol were combined to produce 6.9 g of3-nitro-4-(3,5-difluorophenoxy)-benzonitrile (26.2), mp 132-136° C.

[0195]¹H NMR (400 MHz) (DMSO-d₆) δ 8.72 (d, J=2.0 Hz, 1H); 8.165 (dd,J=8.8, 1.9 Hz, 1H); 7.422 (d, J=8.8 Hz, 1H); 7.227 (m, 1H); 7.103 (m,2H).

Example 27

[0196] This example illustrates the preparation of5-amino-2-(3,5-difluorophenoxy)benzonitrile (27.1).

[0197] Using the method of Example 2,5-nitro-2-(3,5-difluorophenoxy)-benzonitrile (26.1, 6.6 g) was convertedto the title compound (5.47 g, mp 80-84° C.) which was used directly insubsequent reactions.

[0198]¹H NMR (400 MHz) (TFA/DMSO-d₆) δ 11.2 (br s, 2H); 7.083 (d, J=9.2Hz, 1H); 7.077 (d, J=2.8 Hz, 1H); 7.033 (dd, J=9.2, 2.4 Hz, 1H); 6.998(tt, J=9.2, 2.4 Hz, 1H); 6.727 (dd, J=8.4, 2.0 Hz, 2H).

[0199] Similarly, 3-amino-4-(3,5-difluorophenoxy)benzonitrile (27.2) wasprepared from 26.2.

[0200]¹H NMR (400 MHz) (DMSO-d₆) δ 7.14 (d, J=2.0 Hz, 1H); 7.03-6.96 (m,3H); 6.70 (dd, J=8.6, 2.3 Hz, 2H); 5.60 (s, 2H).

[0201] The compounds provided in Table 4 were prepared using 27.1 andcommercially available substituted benzenesulfonyl chlorides and/orusing the intermediates and methods described in the examples above.TABLE 4

Ra Rb Rc Rd mp(° C.) or m/e 27.3 Cl H Cl H 452.7 27.4 H H OCH₃ H 414.827.5 H H I H 510.6 27.6 H H C(O)CH₃ H 482.7 27.7 H H CF₃ H 141-144° C.

Example 28

[0202] This example illustrates the preparation of 28.1.

[0203] 3-Amino-4-(3,5-difluorophenoxy)benzonitrile (201 mg, 27.2) and2,4-dichlorobenzenesulfonyl chloride (302 mg, Maybridge), were combinedin a similar manner to that described in Example 3, then heated to 40°C. The crude product obtained after workup was purified by flashchromatography on silica, eluting with dichloromethane. The productfractions were concentrated and the residue was triturated with diethylether to provide the title compound as a white solid (150 mg, 37%), mp197-200° C.

Example 29

[0204] This example illustrates the preparation of5-nitro-2-(3,5-dichlorophenoxy)-benzonitrile (29.1).

[0205] 2-Chloro-5-nitrobenzonitrile (0.9 g, 5 mmol) and3,5-dichlorophenol were combined using the procedure described inExample 1, to produce 1.5 g of the title compound, mp 188-190° C.

[0206]¹H NMR (400 MHz) (CDCl₃) δ 8.597 (d, J=2.4 Hz, 1H); 8.397 (ddd,J=9.2, 2.8, 0.8 Hz, 1H); 7.360 (dd, J=3.2, 2.0 Hz, 1H); 7.089 (dd,J=1.6, 0.8 Hz, 2H) 7.008 (d, J=9.6 Hz, 1H).

Example 30

[0207] This example illustrates the preparation of5-amino-2-(3,5-dichlorophenoxy)benzonitrile (30.1).

[0208] To a solution of 5-nitro-2-(3,5-dichlorophenoxy)benzonitrile(29.1, 1.5 g) in ethyl acetate (45 mL) was added stannous chloridedihydrate (5.47 g). The mixture was heated to 85° C. for 30 minutesduring which time a thick white precipitate formed. The reaction vesselwas cooled and the mixture was treated with 100 mL of 0.5 N NaGH. Theresulting mixture was extracted twice with ethyl acetate. The combinedorganic extracts were dried over MgSO₄ and concentrated under vacuum toafford the title compound which was used without further purification.MS m/e 279 (M+H).

[0209] The compounds provided in Table 5 were prepared using 30.1 andcommercially available substituted benzenesulfonyl chlorides and/orusing the intermediates and methods described in the examples above.TABLE 5

Ra Rb Rc Rd mp (° C.) 30.2 Cl H Cl H 143-144 30.3 H H CF₃ H 148-149

Example 31

[0210] This example illustrates the preparation of5-nitro-2-(3,5-dimethoxyphenoxy)benzonitrile (31.1).

[0211] 2-Chloro-5-nitrobenzonitrile (5.3 g) and 3,5-dimethoxyphenol (4.5g, Aldrich) were combined using the procedure described in Example 1, toproduce the title compound as a brown solid.

[0212]¹H NMR (400 MHz) (DMSO) δ 8.84 (d, J=2.8, 1H); 8.44 (dd, J=9.3,2.8 Hz, 1H); 7.07 (d, J=9.3 Hz, 1H); 6.51 (s, 3H); 3.76 (s, 6H).

Example 32

[0213] This example illustrates the preparation of5-amino-2-(3,5-dimethoxyphenoxy)benzonitrile (32.1).

[0214] To a solution of 5-nitro-2-(3,5-dichlorophenoxy)benzonitrile(31.1, 8.76 g) in ethyl acetate was added tin chloride (33 g). Themixture was heated to reflux for one hour. The resulting mixture wascooled and 0.5 N sodium hydroxide solution was added to induce theprecipitation of tin salts which were removed by filtration. Thefiltrate was concentrated to provide 7.5 g of the title compound as anorange solid which was used in subsequent reactions withoutpurification.

[0215]¹H NMR (400 MHz) (DMSO-d₆) δ 6.95-6.87 (m, 3H); 6.25 (t, J=2.2 Hz,1H); 6.04 (d, J=2.2 Hz, 2H); 5.49 (s, 2H); 3.70 (s, 6H).

[0216] The compounds provided in Table 6 were prepared using 32.1 andcommercially available substituted benzenesulfonyl chlorides and/orusing the intermediates and methods described in the examples above.TABLE 6

Ra Rb Rc Rd mp (° C.) or m/e 32.2 Cl H Cl H 477 32.3 Cl H CF₃ H 101-105°C. 32.4 H H I H 439 32.5 H H OCH₃ H 162-164° C.

Example 33

[0217] This example illustrates the preparation of3-methoxy-4-(3,5-difluorophenoxy)-nitrobenzene (33.1).

[0218] 4-Chloro-3-methoxynitrobenzene (2.64 g) and 3,5-difluorophenol(Aldrich) were combined using the procedure described in Example 1 andheated to 125° C., to produce the title compound as a thick brown oilwhich solidified on trituration with hexane/methanol to yield 1.33 g of33.1 as a red solid.

[0219]¹H NMR (400 MHz) (DMSO-d₆) δ 7.963 (d, J=2.6 Hz, 1H); 7.903 (dd,J=8.8, 2.7 Hz, 1H); 7.3 16 (d, J=8.8 Hz, 1H); 7.035 (m, 1H); 6.796 (m,2H); 3.909 (s, 3H).

[0220] In a similar manner,3-methoxy-4-(3,5-dichlorophenoxy)nitrobenzene (33.2) and3-methoxy-4-(3,5-dimethoxyphenoxy)nitrobenzene (33.3) were preparedbeginning with 3,5-dichlorophenol and 3,5-dimethoxyphenol, respectively.

[0221] 33.2 3-methoxy-4-(3,5-dichlorophenoxy)nitrobenzene

[0222]¹H NMR (400 MHz) (DMSO-d₆) δ 7.960 (d, J=2.6 Hz, 1H); 7.900 (dd,J=8.9, 2.7 Hz, 1H); 7.394 (t, J=1.7 Hz, 1H); 7.3 10 (d, J=8.8 Hz, 1H);7.107 (t, J=1.4 Hz, 2H); 3.907 (s, 3H).

[0223] 33.3 3-methoxy-4-(3,5-dimethoxyphenoxy)nitrobenzene

[0224]¹H NMR (400 MHz) (DMSO-d₆) δ 7.910 (d, J=2.6 Hz, 1H); 7.862 (dd,J=8.8, 2.6 Hz, 1H); 7.064 (d, J=8.8 Hz, 1H); 6.353 (t, J=2.2 Hz, 1H);6.207 (d, J=2.2 Hz, 2H); 3.927(s, 3H); 3.716 (s, 6H).

[0225] Each of the nitrobenzene derivatives (33.1, 33.2 and 33.3) werereduced to the corresponding aniline derivative using the Raney nickelprocedure of Example 2. The aniline derivatives were then converted tothe compounds shown in Table 7 using commercially available substitutedbenzenesulfonyl chlorides and/or using the intermediates and methodsdescribed in the examples above. TABLE 7

Ar Ra Rb Rc Rd mp(° C.) 33.4 3,5-dichlorophenyl Cl H Cl H 128-131 33.53,5-difluorophenyl H H CF₃ H 141-143 33.6 3,5-dichlorophenyl H H CF₃ H165-166 33.7 3,5-difluorophenyl Cl H Cl H 120-124 33.83,5-difluorophenyl H H OCH₃ H 129-133 33.9 3,5-dimethoxyphenyl Cl H Cl H100-103 33.10 3,5-dimethoxyphenyl Cl H CF₃ H 72-79 33.113,5-dimethoxyphenyl H H OCH₃ H 92-95

Example 34

[0226] This example illustrates the synthesis of5-(4-chlorosulfonyl-2-cyanophenoxy)-3-chloropyridine (34.1).

[0227] Aniline 2.1 (3.11 g, 12.69 mmol) was converted to thecorresponding sulfonyl chloride according to the procedure of R. V.Hoffman (Org. Syn. Coll. Vol., VII, 508-511), yielding 770 mg (18%) of34.1 as a white solid.

[0228] MS ESI m/e: 331.0(M+H)

Example 35

[0229] This example illustrates the synthesis of compound 35.1.

[0230] The title compound was prepared using the method described inExample 3, starting with 4-iodoaniline (136 mg, 0.6197 mmol, AldrichChemical Co.), 5-(4-chlorosulfonyl-2-cyanophenoxy)-3-chlOrOpyridine (136mg, 0.4131 mmol, 34.1), pyridine (49 mg, 0.6 197 mmol), catalytic DMAP,and 3 mL of methylene chloride. The product was obtained as a whitesolid (187 mg, 89%).

[0231]¹H NMR (400 MHz) (d₆-DMSO) δ 10.57 (1H, s); 8.62 (1H, d, J=1.8Hz); 8.60 (1H, d, J=2.2 Hz); 8.28 (1H, d, J=2.4 Hz); 8.12 (1H, d, J=2.2Hz); 7.93 (1H, dd, J₁=8.9 Hz J₂=2.3 Hz); 7.61 (2H, dd, J₁=8 .8 Hz J₂=2.0Hz); 7.17 (1H, d, J=9.0); 6.93 (2H, dd, J₁=8.8 Hz J₂=2.0 Hz). MS ESIm/e: 509.9 (M−H).

Example 36

[0232] This example illustrates the synthesis of compound 36.1.

[0233] The title compound was prepared using the method described inExample 35, starting with 4-acetylaniline (100 mg, 0.31 mmol, AldrichChemical Co.), 5-(4-chlorosulfonyl-2-cyanophenoxy)-3-chloropyridine (62mg, 0.46 mmol), pyridine (36 mg, 0.46 mmol), catalytic DMAP, and 3 mL ofmethylene chloride. The title compound 36.1 was obtained as a whitesolid (120 mg, 92%).

[0234]¹H NMR (400 MHz) (d₆-DMSO) δ 10.53 (1H, s); 8.58 (1H, d, J=1.9Hz); 8.53 (1H, d, J=2.4 Hz); 8.15 (1H, d, J=2.5 Hz); 7.99 (1H, dd,J₁=4.4 Hz J₂=2.2 Hz); 7.86 (1H, dd, J₁=8.8 Hz J₂=2.5 Hz); 7.59 (2H, dd,J₁=8.8 Hz J₂=2.0 Hz); 7.13 (1H, d, J=8.7 Hz); 6.93 (2H, dd, J,=8.8 HzJ₂=2.0 Hz); 2.61 (1H, s). MS ESI m/e: 425.9 (M−H).

Example 37

[0235] This example illustrates the synthesis of5-(4-chlorosulfonyl-2-chlorophenoxy)-3-chloropyridine (37.1).

[0236] Aniline 15.1 (2.10 g, 8.24 mmol) was converted to thecorresponding sulfonyl chloride 37.1, according to the procedure of R.V. Hoffman (Org. Syn. Coll. Vol., VII, 508-511). The title compound wasobtained as a slightly yellow solid (1.65 g, 59%) MS ESI m/e: 338.0(M+H).

Example 38

[0237] This example illustrates the synthesis of compound 38.1.

[0238] The title compound was prepared using the method described inExample 35, starting with 4-iodoaniline (101 mg, 0.46 mmol),S-(4-chlorosulfonyl-2-chlorophenoxyy3 chloropyridine (104 mg, 0.31mmol), pyridine (35 mg, 0.46 mmol), catalytic DMAP, and 3 mL ofmethylene chloride. Compound 38.1 was obtained as a white solid (150 mg,94%).

[0239]¹H NMR (400 MHz) (d₆-DMSO) δ 10.50 (1H, s); 8.55 (1H, d, J=2.1Hz); 8.45 (1H, d, J=2.5 Hz); 7.93 (1H, d, J=2.2 Hz); 7.89(1 H, dd,J₁=4.4 Hz J₂=2.2 Hz); 7.67 (1H, dd, J₁=8.7 Hz J₂=2.2 Hz); 7.61 (2H, dd,J₁=8.8 Hz J₂=2.0 Hz); 7.22 (1H, d, J=8.7 Hz); 6.94 (2H, dd, J₁=8.8 HzJ₂=2.0 Hz). MS ESI m/e: 518.9 (M−H).

Example 39

[0240] This example illustrates the synthesis of compound 39.1.

[0241] The title compound was prepared using the method of Example 38,starting with 4-acetylaniline (55 mg, 0.41 mmol),5-(4-chlorosulfonyl-2-chlorophenoxy)-3-chloropyridine (92 mg, 0.27mmol), pyridine (33 mg, 0.41 mmol), catalytic DMAP, and 3 mL ofinethylene chloride. After workup, 39.1 was obtained as a white solid(130 mg, 93%).

[0242]¹H NMR (400 MHz) (d₆-DMSO) δ 10.94 (1H, s); 8.54 (1H, d, J=2.0Hz); 8.44 (1H, d, J=2.2 Hz); 8.01 (1H, d, J=2.1 Hz); 7.90 (1H, dd,J₁=4.4 Hz J₂=2.2 Hz); 7.86 (2H, dd, J₁=8.8 Hz J₂=1.6 Hz); 7.75 (1H, dd,J₁=8.7 Hz J₂=2.2 Hz); 7.23 (3H, m). MS ESI m/e: 435.0 (M−H).

Example 40

[0243] This example illustrates the preparation of5-(4-amino-2,5-dibromophenoxy)3-chloropyridine (40.1),5-(4-amino-2,3-dibromophenoxy)-3-chloropyridine (40.2), and5-(4-amino-2,3 ,5-tribromophenoxy)-3-chloropyridine (40.3).

[0244] To a 0.1 M solution of 3-bromo-4-(3-chloro-5-pyridyloxy)aniline(20.1) in acetic acid was added bromine (Aldrich). The resultingsolution was stirred for two days. Most of the acetic acid was removedazeotropically using hexanes and the residue was adjusted to pH 6 using4 M aqueous NaGH. The aqueous layer was extracted with ethyl acetate andthe combined organic portions were washed with brine (2X), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theproducts were separated by chromatography to provide5-(4-amino-2,5-dibromophenoxy)-3-chloropyridine (40.1, 32%),5-(4-amino-2,3-dibromophenoxy)-3-chloropyridine (40.2, 15%), and5-(4-amino-2,3 ,5-tribromophenoxy)-3-chloropyridine (40.3, 13%).

[0245] 40.1: ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=1.5 Hz, 1H), 8.22(d, J=2.5 Hz, 1H), 7.46 (d, J=1.0 Hz, 1H), 7.39 (dd, J=2.8, 2.6 Hz, 1H),7.14 (s, 1H), 5.6 (s, 2H). MS (EI): m/z 383 (18, M+H), 382 (10, M+H),381 (75, M+H), 380 (15, M+H), 379 (100, M+H), 378 (7, M+H), 377 (50,M+H).

[0246] 40.2: ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J=2 Hz, 1H), 8.21 (d,J=2.6 Hz, 1H), 7.36 (dd, J=2.4, 2.2 Hz, 1H), 7.32 (dd, J=8.8 Hz, 1H),6.49 (d, J=8.8 Hz, 1H), 5.7 (s, 2H). MS (EI): m/z 383 (18, M+H), 382(10, M+H), 381 (75, M+H), 380 (15, M+H), 379 (100, M+H), 378 (7, M+H),377 (50, M+H).

[0247] 40.3: ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J=2.2 Hz, 1H), 8.26(d, J=2.4 Hz, 1H), 7.63 (s, 1H), 7.48 (dd, J=2.4, 1.9 Hz, 1H), 5.65 (s,2H). MS (EI): m/z 463 (10, M+H), 462 (5, M+H), 461 (50, M+H), 460 (12,M+H), 459 (100, M+H), 458 (12, M+H), 457 (85, M+H), 456 (5, M+H), 455(25, M+H).

Example 41

[0248] This example illustrates the preparation of5-(4-(2,4-dichlorobenzene-sulfonamido)-2,5-dibromophenoxy)-3-chloropyridine(41.1).

[0249]5-(4-(2,4-dichlorobenzenesulfonamido)-2,5-dibrOinOphenOxy)-3-chloropyridinewas prepared in 39% yield from 40.1 and 2,4-dichlorobenzenesulfonylchloride using the method of Example 3.

[0250]¹H NMR (400 MHz, DMSO-d₆) δ 10.6 (s, 1H), 8.47 (bs, 1H), 8.33 (bs,1H), 7.9 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.68 (bs, 1H), 7.61 (d, J=8.8Hz, 1H), 7.57 (s, 1H 7.52 (s, 1H). MS (EI): m/z 593 (6, M+H), 592 (4,M+H), 591 (27, M+H), 590 (10, M+H) 589 (50, M+H), 588 (10, M+H), 587(45, M+H), 586 (3, M+H), 585 (17, M+H).

Example 42

[0251] This example illustrates the preparation of5-(4-amino-2-cyano-3-bromophenoxy))-3-chloropyridine (42.1).

[0252] 3-Cyano-4-(3-chloro-5-pyridyloxy)aniline (see Example 2) wascombined with bromine in acetic acid in a manner similar to thatdescribed in Example 40 to produce5-(4-amino-2-cyano-3-bromophenoxy)-3-chloropyridine (37%) afterchromatography.

[0253] 3H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J=1.8 Hz, 1H), 8.37 (d,J=2.2 Hz, 1H), 7.7 (dd, J=2.2, 1.8 Hz, 1H), 7.13 (1/2ABq, J=9.1 Hz, 1H),7.11 (1/2ABq, J=9.1 Hz, 1H), 5.83 (s, 2H). MS (EI): m/z 328 (30, M+H),327 (13, M+H), 326 (100, M+H),325 (10, M+H), 324 (75, M+H).

Example 43

[0254] This example illustrates the synthesis of5-(4-(2,4-dichlorobenzene-sulfonamido)-2-cyano-3-bromophenoxy)-3-chloropyridine(43.1).

[0255]5-(4-(2,4-dichlorobenzenesulfonamido)-2-cyano-3-bromophenoxy)-3-chloropyridinewas prepared in 28% yield from 42.1 and 2,4-dichlorobenzenesulfonylchloride using the method of Example 3.

[0256]¹H NMR (400 MHz, DMSO-d₆) δ 10.7 (s, 1H), 8.59 (d, J=1.6 Hz, 1H),8.53 (d, J=2 Hz, 1H), 8.05 (bs, 1H), 7.9 (s, 1H), 7.84 (d, J=8.4 Hz,1H), 7.6 (dd, J=8.4, 1.6 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.01 (d, J=9.2Hz, 1H). MS (EI): m/z 537 (20, M+H), 535 (73, M+H), 533 (100, M+H), 531(52, M+H).

Example 44

[0257] This example illustrates the preparation of5-(4-amino-5-bromo-2-inethoxyphenoxy))-3-chloropyridine (44.1).

[0258] To a 0.2M solution of5-(4-amino-2-methoxyphenoxy)-3-chloropyridine (200 mg, 0.8 mmol, 22.1)in CH₂Cl₂ at 0° C. was added 2,4,4,6-tetrabromo-2,5-cyclohexadieneone(334 mg, 0.82 mmol, Lancaster). The resulting solution was stirred for21 hours at ambient temperature. The reaction mixture was diluted withCH₂Cl₂ (50 mL), washed twice with a 2M solution of aqueous sodiumhydroxide (50 mL), once with brine (50 mL), dried over Na₂SO₄, andconcentrated under vacuum. The crude solid was purified by columnchromatography (0-2% MeOH in CH₂Cl₂) to furnish 133 mg (50%) of thetitle compound as a brown solid.

[0259]¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=2.2 Hz, 1H), 8.17 (d, J=2.6Hz, 1H), 7.26 (dd, J=2.3, 1.9 Hz, 1H), 7.24 (s, 1H), 6.64 (s, 1H), 5.38(s, 2H), 3.65 (s, 3H). MS (EI): m/z 329 (80, M+H), 330 (12, M+H), 331(100, M+H), 332 (16, M+H) 333 (28, M+H), 334 (4, M+H).

Example 45

[0260] This example illustrates the preparation of5-(4-(2,4-dichlorobenzenesulfonamido)-5-bromo-2-methoxyphenoxy)-3-chloropyridine(45.1).

[0261]5-(4-(2,4-dichlorobenzenesulfonamido)-5-bromo-2-methoxyphenoxy)-3-chloropyridinewas prepared in 25% yield from 44.1 and 2,4-dichlorobenzenesulfonylchloride using the method of Example 3.

[0262]¹H NMR (400 MHz, DMSO-d₆) δ 10.4 (s, 1H), 8.36 (d, J=1.8 Hz, 1H),8.2 (d, J=2.5 Hz, 1H), 7.9 (d, J=8.6 Hz, 1H), 7.9-7.65 (m, 1H), 7.68(bs, 1H), 7.59 (dd, J=8.6, 2.2 Hz, 1H), 7.45 (s, 1H), 7.42 (dd, J=2.4,1.9 Hz, 1H), 6.99 (s, 1H), 3.65 (s, 3H). MS (EI): m/z 537 (58, M+H), 538(10, M+H), 539 (100, M+H), 540 (20, M+H), 541 (70, M+H), 542 (15, M+H),543 (25, M+H).

Example 46

[0263] This example illustrates-the preparation of5-(4-amino-5-bromo-2-chlorophenoxy))-3-chloropyridine (46.1).

[0264] 5-(4-Amino-5-bromo-2-chlorophenoxy)-3-chloropyridine wassynthesized (43%) in a similar manner as described by Example 44 using3-chloro-4-(3-chloro-5-pyridyloxy)aniline (15.1).

[0265]¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=1.9 Hz, 1H), 8.23 (d, J=2.5Hz, 1H), 7.48 (s, 1H), 7.41 (dd, J=2.4, 2.2 Hz, 1H), 6.98 (s, 1H), 5.62(s, 2H). MS (EI): m/z 333 (55, M+H), 334 (12, M+H), 335 (90, M+H), 336(12, M+H), 337 (40, M+H), 338 (5, M+H).

Example 47

[0266] This example illustrates the preparation of5-(4-(2,4-dichlorobenzene-sulfonamido)-5-bromo-2-chlorophenoxy)-3-chloropyridine(47.1).

[0267]5-(4-(2,4-dichlorobenzenesulfonamido)-5-bromo-2-chlorophenoxy)-3-chloropyridinewas prepared in 17% yield from 46.1 and 2,4-dichlorobenzenesulfonylchloride using the method of Example 3.

[0268]¹H NMR (400 MHz, DMSO-d₆) δ 10.6 (s, 1H), 8.47 (d, J=2.2 Hz, 1H),8.34 (d, J=2.6 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H),7.7 (dd, J=2.3, 2.2 Hz, 1H), 7.6 (dd, J=8.5, 2.0 Hz, 1H), 7.55 (s, 1H),7.47 (s, 1H). MS (EI): m/z 539 (40, M−H), 540 (10, M−H), 541 (100, M−H),542 (20, M−H), 543 (80, M−H), 544 (25, M−H), 545 (35, M−H), 546 (5,M−H).

Example 48

[0269] This example illustrates the preparation of5-(3-chloro-4-amino-2-(N-ethylcarboxamidophenoxy))-3-chloropyridine(48.1) and5-(5-chloro-4-amino-2-(N-ethylcarboxamidophenoxy))-3-chloropyridine(48.2).

[0270] To a 0.1M solution of5-(4-amino-2-(N-ethylcarboxamidophenoxy))-3-chloropyridine, (1 g, 3.6mmol, prepared as described in Ser. No. 09/234,327) in AcOH was addedbromine (194 μL, 3.8 mmol) and the resulting solution was stirred for 2days. Most of the AcOH was azeotropically removed using hexanes and theresulting solution was adjusted to ph 6 using a 4M aqueous solution ofNaOH. The aqueous layer was extracted three times with EtOAc (50 mL) andthe combined organic layers were washed twice with an aqueous brinesolution (100 mL), dried over Na₂SO₄, and concentrated under vacuum. Thecrude solid was purified by chromatography (50-100% EtOAc in hexanes) toseparate the products 48.1 and 48.2 from the starting materials anddibrominated materials. The desired products were thenrechroinatographed (1-3% MeOH in CH₂Cl₂) to furnish 478 mg (36%) of 48.1and 198 mg (15%) of 48.2 as white solids.

[0271] 48.1: ¹H NMR (400 MHz, DM50-d₆) δ 8.37 (t, J=5.2 Hz, 1H), 8.3(bs, 1H), 8.24 (d, J=2.2 Hz, 1H), 7.38 (m, 1H), 6.94 (d, J=8.8 Hz, 1H),6.84 (d, J=8.8 Hz, 1H), 3.1 (pentet, J=7.0 Hz, 2H), 0.91 (t, J=7.1 Hz,3H). MS (EI): m/z 370 (80, M+H), 371 (15, M+H), 372 (100, M+H), 373 (18,M+H), 374 (25, M+H).

[0272] 48.2: ¹H NMR (400 MHz, DMSO-d₆) δ 8.3 (d, J=1.75 Hz, 1H), 8.23(t, J=5.4 Hz, 1H), 8.2 (d, J=2.0 Hz, 1H), 7.34-7.28 (m, 2H), 6.99 (d,J=1.6 Hz, 1H), 3.08 (pentet, J=7.2 Hz, 2H), 0.88 (t, J=7.3 Hz, 3H). MS(EI): m/z 370 (80, M+H), 371 (15, M+H), 372 (100, M+H), 373 (18, M+H),374 (25, M+H).

Example 49

[0273] This example illustrates the preparation of5-(5-bromo-4-(2,4-dichloro-5-methylbenzenesulfonamido)-2-(N-ethylcarboxamido)phenoxy)-3-chloropyridine(49.1).

[0274] The title compound was prepared in 67% yield from 48.1 and2,4-dichloro-5-methylbenzenesulfonyl chloride using the method ofExample 3.

[0275]¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 8.48 (d, J=2.1 Hz, 1H),8.35 (t, J=5.4 Hz, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.85 (bs, 2H), 7.6 (dd,J=2.3, 2.2 Hz, 1H), 7.41 (s, 1H), 7.39 (s, 1H), 3.14 (pentet, J=7.2 Hz,2H), 2.34 (s, 3H), 0.94 (t, J=7.2 Hz, 3H). MS (EI): m/z 597 (8, M−H),596 (25, M−H), 595 (20, M−H), 594 (70, M−H), 593 (30, M−H), 592 (100,M−H), 591 (12, M−H), 590 (50, M−H).

Example 50

[0276] This example illustrates the preparation of5-(5-bromo-4-(2,4-dichlorobenzenesulfonamido)-2-(N-ethylcarboxamido)phenoxy)-3-chloropyridine(50.1).

[0277] The title compound was prepared in 28% yield from 48.1 and2,4-dichloro-benzenesulfonyl chloride using the method of Example 3.

[0278]¹H NMR (400 MHz, DMSO-d₆) δ 10.5 (s, 1H), 8.44 (d, J=2.1 Hz, 1H),8.34 (t, J=5.6 Hz, 1H), 8.31 (d, J=2.3 Hz, 1H), 7.9 (d, J=2.0 Hz, 1H),7.85 (d, J=8.6 Hz, 1H), 7.62 (dd, J=2.4, 2.1 Hz, 1H), 7.59 (dd, J=8.6,2.2 Hz, 1H), 7.41 (s, 1H), 7.38 (s,1H), 3.14 (pentet, J=7.0 Hz, 2H),0.94 (t, J=7.3 Hz, 3H). MS (EI): m/z 585 (8, M+H), 584 (25, M+H), 583(18, M+H), 582 (70, M+H), 581 (25, M+H), 580 (100, M−H), 579 (12, M+H),578 (50, M+H).

Example 51

[0279] This example illustrates the preparation of5-(3-bromo-4-(2,4-dichloro-5-methylbenzenesulfonamido)-2-(N-ethylcarboxamido)phenoxy)-3chloropyridine(51.1).

[0280] The title compound was prepared in 37% yield from 48.2 and2,4-dichloro-5-methylbenzenesulfonyl chloride using the method ofExample 3.

[0281]¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (s, 1H), 8.55 (t, 1H), 8.42 (d,1H), 8.31 (d, 1H), 7.89 (s, 1H), 7.88 (s, 1H), 7.6 (dd, 1H), 7.12 (d,1H), 7.02 (d, 1H), 3.14 (pentet, 2H), 2.35 (s, 3H), 0.94 (t, 3H). MS(EI): m/z 599 (8, M+H), 598 (25, M+H) , 597 (18, M+H), 596 (70, M+H),595 (25, M+H), 594 (100, M−H), 593 (12, M+H), 592 (50, M+H).

Example 52

[0282] This example illustrates the synthesis of5-(5-bromo-4-chlorosulfonyl-2-methoxyphenoxy)-3-chloropyridine (52.1).

[0283] Compound 44.1 (1.20 g, 3.66 mmol) was converted to the titlecompound using the general procedure of R. V. Hoffman (Org. Syn. Coll.Vol., VII, 508-511), to provide 1.26 g (84%) of 52.1 as a clear oilwhich was carried on without purification.

[0284] MS ESI m/e: 412.0(M+H).

Example 53

[0285] This example illustrates the preparation of 53.1.

[0286] 4-Chloroaniline (73 mg, 0.57 mmol, Aldrich Chemical Co.),5-(5-bromo-4-chlorosulfonyl-2-methoxyphenoxy)-3-chloropyridine (236 mg,0.57 mmol); pyridine (45 mg, 0.57 mmol), catalytic DMAP, and 2 mL ofmethylene chloride were combined using the general method of Example 35.The title compound was obtained (245 mg, 85%) as a white solid.

[0287]¹H NMR (400 MHz) (d₆-DMSO) δ 10.80 (1H, s); 8.43 (1H, d, J=2.0Hz); 8.30 (1H, d, J=2.4 Hz); 7.74 (1H, s); 7.64 (1H, dd, J=4.4 Hz, 2.2Hz); 7.52 (1H, s); 7.31 (2H, dd, J=8.8 Hz, 2.1 Hz); 7.14 (1H, dd, J=8.8Hz, 2.1 Hz); 3.83 (3H, s). MS ESI m/e: 435.0 (M−H).

Example 54

[0288] This example illustrates the preparation of 54.1.

[0289] In a manner similar to that described in Example 53,4-iodoaniline (83 mg, 0.38 mmol),5-(5-bromo-4-chlorosulfonyl-2-methoxyphenoxy)-3-chloropyridine (155 mg,0.38 mmol), pyridine (30 mg, 0.38 mmol), catalytic DMAP, and 2 mL ofmethylene chloride were combined and stirred. After workup, the titlecompound was obtained (162 mg, 73%) as a white solid.

[0290]¹H NMR (400 MHz) (d₆-DMSO) δ 10.80 (1H, s); 8.43 (1H, d, J=2.0Hz); 8.31 (1H, d, J=2.4 Hz); 7.75 (1H, s); 7.64 (1H, dd, J=4.4 Hz, 2.2Hz); 7.58 (2H, m); 7.51 (1H, s) 6.95 (1H, dd, J=8.6 Hz, 2.2 Hz); 3.84(3H, s). MS ESI m/e: 592.8 (M−H).

Example 55

[0291] This example illustrates the preparation of 55.1.

[0292] In a manner similar to that described in Example 53,4-acetylaniline (69 mg, 0.51 mmol),5-(5-bromo-4-chlorosulfonyl-2-methoxyphenoxy)-3-chloropyridine (210 mg,0.51 mmol), pyridine (40 mg, 0.51 mmol), catalytic DMAP, and 2 mL ofmethylene chloride were combined and stirred. After workup, the titlecompound was obtained (192 mg, 74%) as a white solid.

[0293]¹H NMR (400 MHz) (d₆-DMSO) δ 10.80 (1H, s); 8.43 (1H, d, J=2.0Hz); 8.31 (1H, d, J=2.4 Hz); 7.75 (1H, s); 7.64 (1H, dd, J=4.4 Hz, 2.2Hz); 7.58 (2H,m); 7.51 (1H, s) 6.95 (1H, dd, J=8.6 Hz, 2.2 Hz); 3.84(3H, s). MS ESI in/e: 509.0 (M−H).

Example 56

[0294] This example illustrates the preparation of3-chloro-4-(2-naphthylxoy)nitrobenzene (56.1).

[0295] To a 250 mL flask, were added 3-chloro-4-fluoro-nitrobenzene(Aldrich)(5.0 g, 28 mmol), 2-naphtol (Aldrich)(4.Sg, 31 mmol), Cs₂CO₃(Aldrich)(9.7 g, 30 mmol) and DME (80 mL). The mixture was heated at100° C. overnight. After removal of DMF under vacuum, the mixture waspoured into water and extracted with dichloromethane. The organicsolution was then washed with brine, dried over magnesium sulfate. Afterfiltration, the filtrate was concentrated under vacuum to give a crudeproduct, which was then chromatographed with eluent (30%dichloromethane/hexanes) to give the title compound (6.8 g, 24 mmol,86%).

Example 57

[0296] This example illustrates the preparation of compounds 57.1, 57.2,57.3 and 57.4.

[0297] Compound 56.1 was reduced to the corresponding aniline derivative(57.1) using the procedure of Example 2, and converted to the compoundsin Table 8 using commercially available substituted benzenesulfonylchlorides and/or using the intermediates and methods described in theexamples above. TABLE 8

Ra Rb Rc Rd m/e 57.2 Cl H Cl H 476 57.3 Cl H I H 534 57.4 H H OCH₃ H 438

Example 58

[0298] This illustrates the synthesis of3-chloro-(2,4-dichlorobenzene-sulfonamido)benzene (58.1).

[0299] The title compound was prepared using the method described inExample 3, starting with 800 mg (6.29 mmol) of 3-chloroaniline, 1.53 g(6.29 mmol) of 2,4-dichlorosulfonylchloride, 497 mg (6.29 mmol) ofpyridine, catalytic DMAP, and 10 mL of inethylene chloride. The titlecompound was obtained as a white foam (928 mg, 44%).

[0300] MS ESI m/e: 334.0 (M−H).

Example 59

[0301] This example illustrates the synthesis of compound 59.1.

[0302] A round-bottomed flask was charged with 330 mg (0.99 mmol) of3-chloro-(2,4-dichlorobenzenesulfonamido)benzene (58.1), 397 mg (2.97mmol, Aldrich Chemical Co.) of anhydrous aluminum trichloride, and 2 mLof dry dichloroethane. Then 210 mg (1.19 mmol, Aldrich Chemical Co.) of3,5-difluorobenzoyl chloride was added dropwise and the deep redsolution was allowed to stir at room temperature overnight. The reactionwas then diluted with 30 mL of methylene chloride, washed consecutivelywith 2N HCl and brine, dried over MgSO₄, and concentrated to a dark oil.This was further purified by silica gel flash chromatography (elutingwith 1:24 ethyl acetate:methylene chloride). The resulting clear glazewas recrystallized from ether/hexanes to yield 273 mg (58%) of a whitesolid.

[0303]¹H NMR (400 MHz) (d₆-DMSO) δ 8.15 (1H, d, J=8.5 Hz); 7.91 (1H, d,J=2.1 Hz); 7.68 (1H, dd, J=8.6 Hz, 2.1 Hz); 7.63 (1H, t, J=8.6 Hz); 7.46(1H, d, J=8.4 Hz); 7.31 (2H, dd, J=7.8 Hz, 2.1 Hz); 7.23 (1H, d, J=1.9Hz); 7.17 (1H, dd, J=8.4 Hz, 2.2 Hz). MS ESI m/e: 473.9 (M−H).

Example 60

[0304] This illustrates the synthesis of compound 60.1.

[0305] The title compound was prepared using the method of Example 59,starting with 286 mg (0.85 mmol) of3-chloro-(2,4-dichlorobenzenesulfonamido)benzene (58.1), 341 mg (1.02mmol) of anhydrous aluminum trichloride, 214 mg (1.02 mmol, AldrichChemical Co.) of 3,5-dichlorobenzoyl chloride, and 2 m1L of drydichloroethane. The title compound was obtained as a white solid (139mg, 32%).

[0306]¹H NMR (400 MHz) (d₆-DMSO) δ 11.49 (1H, s) 8.15 (1H, d, J=8.6 Hz);7.97 (1H, d, J=3.8 Hz); 7.91 (1H, d, J=2.1 Hz ); 7.69 (1H, dd, J=8.5 Hz,2.0 Hz); 7.58 (2H, d, J=1.9 Hz); 7.47 (1H, d, 1=8.4 Hz); 7.24 (1H, d,J=2.0 Hz); 7.17 (1H, dd, J=8.4 Hz, 2.1 Hz). MS ESI m/e: 505.9 (M−H).

Example 61

[0307] This illustrates the synthesis of compound 61.1.

[0308] Biaryl ketone 59.1 (103 mg, 0.22 mmol) was reduced to themethylene compound 61.1 according to the procedure of West, et. al., J.Org. Chem., 38(15): 2675-2681 (1973). The title compound was obtained asa white solid (86 mg, 86%).

[0309]¹H NMR (400 MHz) (d₆-DMSO) δ 10.96 (1H, s) 8.05 (1H, d, J=8.6 Hz);7.87 (1H, d, J=2.0 Hz); 7.63 (1H, dd, J=8.5 Hz, 2.1 Hz); 7.23 (1H, d,J=8.5 Hz); 7.14 (1H, d, J=2.2 Hz); 7.02 (2H, m); 7.17 (2H, m). MS ESIm/e: 460.0 (M−H).

Example 62

[0310] This example illustrates the preparation of2-chloro-4-(3-chloro-5-pyridyloxy)-nitrobenzene 62.1.

[0311] 5-Chloro-3-pyridinol (5 g, Aldrich) and 2,4-dichloronitrobenzene(7.4 g, Aldrich) were combined as described in Example 1. The titlecompound was isolated as the minor product using gravity chromatographyon silica eluting with 10% ethyl acetate/hexanes.

[0312]¹H NMR (400 MHz) (DMSO-d₆) δ 8.53 (s, 1H); 8.4 (s, 1H); 8.0 (d,J=8.9 Hz, 1H); 7.44 (t, J=1.9 Hz, 1H); 7.26 (d, 1=1.5 Hz, 1H); 7.14 (d,1=2.7 Hz, 1H); 6.99 (dd, 1=9.0, 2.6 Hz, 1H) 1.6 (impurity).

Example 63

[0313] This example illustrates the preparation of2-chloro-4-(3-chloro-5-pyridyloxy)-aniline 63.1.

[0314] Compound 62.1 was reduced using the method of Example 2 toprovide the title compound as a yellow solid.

[0315]¹H NMR (400 MHz) (DMSO) δ 8.33 (d, J=2.1 Hz, 1H); 8.25 (d, J=2.4Hz, 1H); 7.41 (t, J=2.2 Hz, 1H); 7.12 (d, J=2.6 Hz, 1H); 6.91 (dd,J=2.6, 8.8 Hz, 1H); 6.84 (d, J=8.8 Hz, 1H); 5.35 (s, 2H).

Example 64

[0316] This example illustrates the preparation of 64.1.

[0317] Compound 63.1 and 2,4-dichlorobenzenesulfonyl chloride werecombined with pyridine and DMAP using the method described in Example 3.The crude product was purified by flash chromatography on silica elutingwith dichloromethane. The resulting product was then triturated indiethyl ether/hexanes to furnish the title compound as a white solid. MSESI m/e: 461 (M−H).

Example 65

[0318] This example illustrates the preparation of 65.1.

[0319] Compound 63.1 and 3,4-dichlorobenzenesulfonyl chloride werecombined with pyridine and DMAP using the method described in Example 3.The crude product was purified by flash chromatography on silica elutingwith 5% ethyl acetate/dichloromethane. The resulting product was thentriturated in hexanes to furnish the title compound as a white solid. MSESI m/e: 461 (M−H).

Example 66

[0320] This example illustrates the preparation of 66.1.

[0321] Compound 63.1 and 4-iodobenzenesulfonyl chloride were combinedwith pyridine and DMAP using the method described in Example 3. Thecrude product was purified by flash chromatography on silica elutingwith dichloromethane. The resulting product was then triturated inhexanes to furnish the title compound as a white solid. MS ESI m/e: 519(M−H).

Example 67

[0322] This example illustrates the preparation of 67.1.

[0323] Compound 63.1 and 2-chloro-4-trifluoroinethylbenzenesulfonylchloride were combined with pyridine and DMAP using the method describedin Example 3. The crude product was purified by flash chromatography onsilica eluting with 5% ethyl acetate/dichloromethane. The resultingproduct was then triturated in hexanes to furnish the title compound asa white solid. MS ESI m/e: 495 (M−H).

Example 68

[0324] This example illustrates the preparation of2-chloro-4-(3-pyridyloxy)nitrobenzene (68.1).

[0325] 2,4-Dichloronitrobenzene (10.2 g, Aldrich) and 3-hydroxypyridine(5 g, Aldrich) were combined using the method of Example 1, to providethe 0.82 g of the title compound as a yellow solid.

[0326]¹H NMR (400 MHz) (CDCl₃) δ 8.58 (s, 1H); 8.52 (s, 1H); 8.0 (d,J=9.0 Hz, 1H); 7.44 (s, 2H); 7.10 (d, J=2.6 Hz, 1 H) 6.96 (dd, J=9.0,6.65 Hz).

Example 69

[0327] This example illustrates the preparation of2-chloro-4-(3-pyridyloxy)aniline.

[0328] Compound 68.1 was reduced using the method of Example 2 toprovide the title compound as a brown oil, which was used withoutfurther purification.

[0329]¹H NMR (400 MHz) (DMSO) δ 8.29-8.26 (m, 2H); 7.35 (dd, J=4.6, 8.4Hz, 1H); 7.29-7.26 (m, 1H); 7.04 (d, J=2.0 Hz, 1H); 6.85-6.84 (m, 2H);5.29 (s, 2H).

Example 70

[0330] This example illustrates the preparation of 70.1.

[0331] Compound 69.1 and 2,4-dichlorobenzenesulfonyl chloride werecombined with pyridine and DMAP using the method described in Example 3.The crude product was purified by flash chromatography on silica elutingwith 5% ethyl acetate/dichloromethane. The resulting product was thentriturated in diethyl ether to furnish the title compound as a whitesolid. MS ESI m/e: 429 (M−H).

Example 71

[0332] This example illustrates the preparation of 71.1.

[0333] Compound 69.1 and 4-iodobenzenesulfonyl chloride were combinedwith pyridine and DMAP using the method described in Example 3. Thecrude product was purified using flash chromatography on silica elutingwith 5-20% ethyl acetate/dichloromethane. The resulting product was thentriturated in diethyl ether to furnish the title compound as a whitesolid. MS ESI m/e: 485 (M−H).

Example 72

[0334] This example illustrates the preparation of 72.1.

[0335] To a solution of 3,4-dichlorothiophenol (0.87 mL) and4-fluoro-3-chloronitrobenzene (1.2 g) in THF (12 mL) was added asolution of potassium t-butoxide in THF (1 M, 3.7 mL). Ethanol was addedto form a precipitate and the mixture was heated to dissolve the solid.The mixture was then cooled to ambient temperature and water was added.The resulting solids were collected by filtration and washed with water.The product was dissolved in methylene chloride, dried over magnesiumsulfate, filtered and concentrated to provide a yellow nitrointermediate (2.08 g).

[0336] SnCl₂ hexahydrate (7 g) was added to a solution of theintermediate nitro compound in ethyl acetate (40 mL) at 85° C. After 12hr, the reaction was treated with 420 mL of 0.5 N NaOH solution anddiluted with EtOAc (100 mL). The milky suspension was filtered throughCelite and rinsed with additional EtOAc. The layers were separated andthe water layer was extracted with additional EtOAc. The combinedorganic portions were dried over MgSO₄, filtered and concentrated undervacuum to provide the aniline derivative 72.1, which was used withoutpurification.

[0337] The compounds provided in Table 9 were prepared using 72.1 andcommercially available substituted benzenesulfonyl chlorides and/orusing the intermediates and methods described in the examples above.TABLE 9

Ra Rb Rc Rd m/e (M − H) 72.2 H Cl Cl H 510 72.3 Cl H Cl H 510 72.4 H H IH 568

[0338] Compound 72.3 was converted to the corresponding biaryl sulfoxide(72.5, m/e 526) and biaryl sulfone (72.6, m/e 542) using an oxoneprocedure (see, for example, Trost, et al., Tetrahedron Lett., 22:1287(1981) and Webb, Tetrahedron Lett., 35:3457-3460 (1994)). Similarly,compound 72.2 was converted to the biaryl sulfoxide (72.7, m/e 526)using a routine oxidation with mCPBA.

Example 73

[0339] This example illustrates the preparation of 73.4 through 73.9.

[0340] 2,3 dichloronitrobenzene (19.04 g) was suspended in 40% Na₂CS₃solution in water (66 ml) with 5 ml of ethanol and heated at 130° C.bath temperature for 3 days. After cooling, the residue was diluted inwater and acidified with 5N HCl (caution: foaming gas evolution). Thetan solids were collected by filtration, rinsed with water and driedunder vacuum to give 19.9 g of an intermediate complex (73.1). The crude73.1 (6.03 g) was added to neat sulfuryl chloride (20 ml) cautiouslyover about 5 minutes. The mixture was then heated at 50° C. Thecharacter of the solid changed but did not dissolve. The reaction wasquenched by pouring onto ice. The ice mixture was stirred until theinitial heavy dark oil solidified. The solids were collected byfiltration, dissolved in ethyl ether and washed with water. The productwas purified by flash chromatography using hexane, then 20% methylenechloride/hexane to afford 3.2 g of a 2,7-dichlorobenzothiazole (73.2) asa low melting solid.

[0341]¹H NMR (CDCl₃) δ 7.823 (d, J=8.4 Hz), 7.417 (t, J=8.4 Hz), 7.371(d, J=8.4 Hz). Anal. calc: 41.20% C, 1.48% H, 6.86% N; found: 41.06% C,1.46% H, 6.75% N.

[0342] 3-Chloro-4-mercapto nitrobenzene (prepared by the method of Priceand Stacy, J. Amer. Chem. Soc. 68, 498-500 (1946)) (1.33 g) and2,7-dichlorobenzothiazole (73.2) (1.43 g) were dissolved in ethanol (20ml) with heating. Pyridine (1.1 g, 2 eq) was added. After a solidformed, additional ethanol (20 ml) was added and the mixture maintainedat 50° C. overnight. The solid was collected by filtration and rinsedwith water. The solids were dried as a solution in methylene chlorideand concentrated to afford the nitro compound 73.3 (2.22 g) as anoff-white solid. (mp 210-212° C.)

[0343]¹H NMR (DMSO) δ 8.544 (d, J=2.4 Hz, 1H), 8.273 (dd, J=8.8, 2.5 Hz,1H) 8.081 (d, J=8.6 Hz, 1H) 7.961 (dd, J=6.3, 2.4 Hz, 1H), 7.60 (m, 2H).

[0344] Using the method of example 32, the nitro derivative 73.3 wasconverted to the corresponding aniline (73.4). Flash chromatography gavea white solid. (mp 165-167° C.).

[0345]¹H NMR (DMSO) δ 7.775 (d, J=8.4 Hz, 1H), 7.606 (d, J=8.0 Hz, 1H),7.367 (t, J=8.0 Hz, 1H), 7.265 (d, J=8.0 Hz, 1H), 6.931 (d, J=2.0 Hz,1H), 6.672 (dd, J=8.4, 2.4 Hz, 1H), 4.15 (br s, 2H). ESI MS 327 (M+H).Anal. calcd. 47.71% C, 2.46% H, 8.56% N; found: 47.93% C, 2.48% H, 8.47%N.

[0346] Reaction of 2-chloro-4-trifluoromethylbenzene sulfonyl chloridewith aniline 73.4 according to the method of Example 3 gave sulfonamide73.5 (see Table 10).

[0347]¹H NMR (DMSO) δ 11.712 (br s, 1H) 8.377 (d, J=8.4 Hz, 1H), 8.187(d, J=2 Hz, 1H), 7.995 (dd, J=8.4, 1.2 Hz, 1H), 7.880 (d, J=8.4 Hz, 1H),7.822 (dd, 7.2, 2.0 Hz, 1H), 7.509 (t, J=8.0 Hz, 1H), 7.474 (dd, J=7.6,2.0 Hz, 1H), 7.443 (d, J=2.4 Hz, 1H), 7.256 (dd, J=8.8, 2.4 Hz, 1H). MS(M+H) 569; MS (M−H) 567. Anal. calcd. 42.15% C, 1.77% H, 4.92% N; found:42.30% C, 1.76% H, 4.94% N.

[0348] The additional compounds provide in Table 10 were preparedsimilarly using aniline 73.4 and the corresponding sulfonyl chloridesusing the method of Example 3. TABLE 10

Ra Rb Rc Rd m/e (M − H) 73.5 Cl H CF₃ H 567 73.6 H Cl Cl H 533 73.7 Cl HCl H 533 73.8 H H I H 591 73.9 Cl H Cl Me 547

Example 74

[0349] The following benzenesulfonyl chlorides were prepared by theprocedure of R. V. Hoffman (Org. Syn. Coll. Vol. VII, 508-511) from thecorresponding commercially available anilines and used to make theindicated examples.

[0350] 74a 2-chloro-4-t-butylbenzenesulfonyl chloride. yield 34%

[0351] for examples 76.8 and 79.9

[0352]¹H NMR (CDCl₃) δ 8.06 (1H, d, J=8.4 Hz), 7.62 (1H, s), 7.48 (1H,d, J=8.4 Hz), 1.37 (9H, s) m.p. 68.8° C.

[0353] 74b 2-trifluoromethyl-4-chlorobenzenesulfonyl chloride. yield 76%as a solid.

[0354] for examples 176 and 347

[0355]¹H NMR (CDCl₃) δ 8.325 (d, J=8.4 Hz, 1H), 7.966 (br s, 1H), 7.829(br d, J=8.4 Hz, 1H) m.p. 37.0° C.

[0356] 74c 2-chloro-4-methylbenzenesulfonyl chloride. yield 47% as anoil.

[0357] for examples 76.9, 79.8 and 351.

[0358]¹H NMR (CDCl₃) δ 8.02 (1H, d, J=8.8 Hz), 7.46 (1H, s), 7.28 (1H,d, J=8.8 Hz), 2.47 (3H, s).

Example 75

[0359] This illustrates the synthesis of compound 75.

[0360] By the method of example 201, 2-chlorobenzoxazole (5 g) and2-chloro-4-nitroaniline (6.1 g) were coupled to provide nitro compound75.1 (2.6 g) as a yellow solid.

[0361]¹H NMR (d6-acetone) δ 9.514 (s, 1H), 9.01 (d, J=9 Hz, 1H), 8.4 (s,1H), 8.37 (dd, J=8.4, 2 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.52 (d, J=8Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.28 (t, J=7.6 Hz, 1H). MS (M−H) 288;(2M−2H+Na) 599.

[0362] Reduction by the method of example 32 gave the aniline 75 (93%)as a grey solid.

[0363]¹H NMR (d6-acetone) δ 8.45 (br s, 1H), 7.796 (d, J=8.4 Hz, 1H),7.353 (d, J=7.6 Hz, 1H), 7.335)d, J=7.6 Hz, 1H), 7.191 (t, J=7.6 Hz,1H), 7.088 (t, J=8 Hz, 1H), 6.846 (d, J=2.4 Hz, 1H), 6.673 (dd, J=8.8,2.4 Hz, 1H), 4.912 (br s, 2H). MS (M+H) 260.1.

Example 76

[0364] This example illustrates the preparation of 76.2 and sulfonamidesderived from it.

[0365] 3,5-dichloro-4-mercapto nitrobenzene (prepared by the method ofPrice and Stacy, J. Amer. Chem. Soc. 68, 498-500 (1946)) (0.65 g) and2,7-dichlorobenzothiazole (73.2) were combined by the method of Example73, to afford the nitro derivative (76.1) as a yellow solid (0.95 g).

[0366]¹H NMR (DMSO) δ 8.587 (s, 2H), 7.852 (m, 1H), 7.54 (m 2H). Anal.calcd: 39.87% C, 1.29% H, 7.15% N; found 39.62% C, 1.21% H, 7.00% N.

[0367] Reduction of the nitro derivative (76.1) (0.92 g) by the methodof example 32 gave the aniline (76.2) (0.76 g) after flashchromatography.

[0368]¹H NMR (DMSO) δ 7.822 (d, J=8 Hz, 1H) 7.509 (t, J=8 Hz, 1H), 7.465(d, J=6.8 Hz, 1H) 6.882 (s, 2H), 6.529 (br s, 2H). MS (M+H) 361. Anal.calcd: 43.177% C, 1.95% H, 7.74% N; found: 43.10% C, 2.05% H, 7.65% N.

[0369] Reaction of the aniline 76.2 according to the method of example 3with various sulfonyl chlorides gave the sulfonamides of Table 11. TABLE11

Ra Rb Rc Rd m/e (M − H) 76.3 Cl H CF₃ H 601 76.4 H H t-Bu H 76.5 Cl H ClH 567 76.6 Cl H H H 535 (M + H) 76.7 H H H H 76.8 Cl H t-Bu H 589 76.9Cl H Me H 547

Example 76.3

[0370]¹H NMR (DMSO) δ 11.96 (br s, 1H) 8.417 (d, J=8.4 Hz, 1H), 8.209(s, 2H), 8.013 (d, J=8 Hz, 1H), 7.819 (d, J=6.8 Hz, 1H), 7.514 (m, 2 H),7.411 (s, 2H). Anal. calcd: 39.75% C, 1.50% H, 4.64% N; found: 39.48% C,1.73% H, 4.37% N. MS (M−H) 601.

Example 76.4

[0371] Anal. calcd. for M+0.5 H₂O: 48.72% C, 3.56% H, 4.94% N; found:48.80% C, 3.68% H, 4.78% N.

Example 76.5

[0372]¹H NMR (DMSO) δ 11.83 (br s, 1H) 8.212 (d, J=8.4 Hz, 1H), 7.962(d, J=2H, 1H), 7.827 (dd, J=6.8, 2 Hz, 1H), 7.723 (dd, J=8.5, 2.1 Hz,1H), 7.518 (t, Hz, 1H), 7.492 (dd, J=7.8, 2.0 Hz, 1H), 7.385 (s, 2H). MS(M−H) 567. mp 216° C. Anal. calcd: 39.98% C, 1.59% H, 4.91% N; found:39.81% C, 1.59% H, 4.85% N.

Example 76.6

[0373]¹H NMR (DMSO) δ 11.72 (br s, 1H), 8.222 (d, J=8 Hz, 1H), 7.822(dd, J=7.2, 2.0 Hz, 1H), 7.730 (d, J=4 Hz, 2H), 7.636 (m, 1H), 7.516 (t,J=8 Hz, 1H), 7.490 (d, J=8 Hz, 1H), 7.379 (s, 2H). MS (M+H) 535.

Example 76.7

[0374]¹H NMR (DMSO) δ 11.38 (br s, 1H), 8.906 (d, J=8 Hz, 2H), 7.827(dd, J=7.2, 2.0 Hz, 1H), 7.721 (t, J=6.8 Hz, 1H), 7.655 (t, J=8 Hz, 2H),7.519 (t, J=8 Hz, 1H), 7.493 (d, J=6.8 Hz, 1H), 7.412 (s, 2H).

Example 76.8

[0375]¹H NMR (DMSO) δ 11.70 (1H, s), 8.13 (1H, d, 8.4), 7.80-7.87 (1H,m), 7.63-7.71 (2H, m), 7.48-7.55 (2H, m), 7.39 (2H, s). MS (M−H) 589. mp131.3° C. Anal. calcd: C, 46.63, H 3.06, N, 4.73; found C, 48.09, H3.65, N, 4.35.

Example 76.9

[0376]¹H NMR (DMSO) δ 11.70 (1H, s), 8.07-8.20 (1H, m), 7.80-7.93 (1H,m), 7.35-7.65 (6H, m). MS (M−H) 546.8. mp 220.9° C.

Example 77

[0377] This example illustrates the preparation of anilines 77.7, 77.8and 77.9

[0378] In analogy to the procedures of Weinstock et. al (J. Med. Chem.30:1166-1176 (1987), conc. sulfuric acid (8.74 g) was added slowly to asolution of 5-chloro-2-methylaniline (25 g) in chlorobenzene (120 mL) toform a thick slurry. Powdered NaSCN (18.6 g) was added. The mixture washeated at 110° C. for one hour then maintained at 50° C. overnight.After dilution with hexane (300 mL), the solid was collected byfiltration, washed with hot water and rinsed with ethyl ether to afford15.65 g of intermediate thiourea 77.1 which was used directly in thenext step.

[0379] Preparation of 2-amino-4-methyl-7-chlorobenzothiazole (77.2).

[0380] Bromine (25.44 g) was added to a suspension of 77.1 (15 g) inchloroform (110 mL) maintained below +10° C. After the addition wascomplete, the reaction was allowed to warm to RT then heated at refluxfor 30 minutes. After cooling, the orange solid was collected byfiltration and suspended in acetone (100 mL) which discharges theremaining color. Solids were collected by filtration and rinsed withethyl ether to afford the HBr salt.

[0381]¹H NMR (DMSO) δ 7.182 (d, J=8 Hz, 1H), 7.137 (d, J=8 Hz, 1H), 2.40(s, 3H).

[0382] The salt was suspended in water at 95° C. The pH of thesuspension was adjusted to pH 9 with 0.5 N NaOH. After cooling, thesolids were collected by filtration, rinsed with water and dissolved inethylether/methylene chloride. The organic layer was dried overmagnesium sulfate. After concentration,2-amino-4-methyl-7-chlorobenzothiazole (77.2) (7.47 g) was obtained as awhite solid.

[0383] MS (M+H) 199. Anal. calcd.: 48.36% C, 3.55% H, 14.10% N; found:48.29% C, 3.55% H, 14.01% N.

[0384] Preparation of 2-7-dichloro-4-methyl-benzothiazole (77.3)

[0385] To a slurry of 2-amino-4-methyl-7-chlorobenzothiazole(77.2) (6.37g) in H3PO4 (85%, 213 ml) in a 500 ml 3-necked flask with mechanicalstirring and an internal temperature of <−10° C., was added dropwise asolution of NaNO₂ (6.87 g) in water (11 ml). The mixture was warmed to0° for 30 minutes and then recooled. The slurry was then slowly added toa cold (˜−5° C.) solution of CuSO4.5 H₂O (32 g) and NaCl (40 g) in water(128 ml) with vigorous mechanical stirring. After the foaming subsidesand warming to RT, the solids were collected by filtration and rinsedwith water. The solids were dissolved in ether leaving some insolubleresidue. The ether solution was washed with water, and sodiumbicarbonate solution. After the organic layer was concentrated, theresidue was purified by flash chromatography with 10% methylene chloridein hexane to afford 2-chloro-4-methyl-7-chlorobenzothiazole (77.3) (4.48g).

[0386]¹H NMR (CDCl₃) δ 7.288 (d, J=8 Hz, 1H), 7.231 (dq, J=8. 0.8 Hz,1H), 2.651 (d, J=0.8 Hz, 3H). Anal. calcd.: 44.06% C, 2.31% H, 6.42% N;found: 44.16% C, 2.34% H, 6.32% N.

[0387] Coupling of 77.3 (0.65 g) with 3,5-dichloro-4-mercaptonitrobenzene by the method of example 73 gave after flash chromatographythe nitro derivative 77.4 (0.97 g) as a yellow solid.

[0388] 1H NMR (DMSO) δ 8.394 (s, 2H), 7.237 (d, J=8 Hz, 1H), 7.209 (d,J=8 Hz, 1H), 2.621 (s, 3H). MS (M+H) 405.

[0389] Coupling of 77.3 (0.7 g) with 3-chloro-4-mercapto nitrobenzene bythe method of example 73 gave the nitro derivative 77.5 (1.02 g) as ayellow solid.

[0390]¹H NMR (DMSO) δ 8.535 (br s, 1H), 8.261 (dd, J=8.4, 2 Hz, 1H),8.040 (d, J=8.4 Hz, 1H), 7.496 (d, J=8.4 Hz, 1H), 7.419 (d, J=8.4 Hz,1H), 2.601 (s, 3H). MS (M+H) 371. Anal. calcd.: 45.40% C, 2.18% H, 7.57%N; found: 45.25% C, 2.23% H, 7.49% N.

[0391] Coupling of 77.3 (1.12 g) with 3-fluoro-4-mercapto nitrobenzeneby the method of example 73 gave after flash chromatography the nitroderivative 77.6 (SY1904-2) (1.8 g) ¹H NMR

[0392] Reduction of 77.4 (0.96 g) with tin dichloride by the method ofexample 32 gave the aniline (77.7) (0.84 g) used directly in laterreactions:

[0393]¹H NMR (DMSO) δ 7.352 (d, J=8 Hz, 1H), 7.322 (d, J=8 Hz, 1H),6.884 (s, 2H), 6.533 (br s, 2H), 2.565 (s, 3H).

[0394] Reduction of 77.5 (1.13 g) with tin dichloride by the method ofexample 32 gave the aniline (77.8) (1.04 g) used directly in laterreactions:

[0395]¹H NMR (DMSO) δ 7.543 (d, J=8.4 Hz, 1H), 7.329 (d, J=8 Hz, 1H),7.301 (d, J=8 Hz, 1H), 6.889 (d, J=2 Hz, 1H), 6.663 (dd, J=8.4, 2.4 Hz,1H), 6.231 (br s, 2H), 2.557 (s, 3H). MS (M+H) 341. Anal. calcd. forM+0.25 H₂O: 48.63% C, 3.06% H, 8.10% N; found: 48.67% C, 3.06% H, 7.96%N.

[0396] Reduction of 77.6 (1.75 g) with tin dichloride by the method ofexample 32 gave after chromatography the aniline (77.9) (1.2 g)

[0397]¹H NMR: δ 7.43 (1H, t, 8.3), 7.30-7.37 (2H, m), 6.53-6.58 (2H, m),6.28 (2H, s).

Example 78

[0398] Treatment of the anilines 77.7, 77.8 or 77.9 by the method ofexample 3 with various sulfonyl chlorides gave the sulfonamides of Table12. TABLE 12

X Y Ra Rb Rc Rd m/e (M − H) 78.1 Cl Cl Cl H Cl H 581 78.2 Cl Cl Cl H CF₃H 615 78.3 Cl Cl Cl H Cl Me 595 78.4 Cl H Cl H CF₃ H 581 78.5 Cl H Cl HCl H 565 78.6 F H Cl H CF₃ H 565 78.7 F H Cl H Cl H 531

Example 78.1

[0399]¹H NMR (DMSO) δ 11.813 (br s, 1H), 8.208 (d, J=8.8 Hz, 1H), 7.951(d, J=2 Hz, 1H), 7.716 (dd, J=8.4, 2 Hz, 1H), 7.396 (s, 2H), 7.377 (d,J=8.4 Hz, 1H), 7.334 (d, J=8 Hz, 1H), 2.516 (s, 3H). MS (M−H) 581. Anal.calcd. for M+H₂O: 39.85% C, 2.17% H, 4.65% N; found: 40.10% C, 1.89% H,4.57% N.

Example 78.2

[0400]¹H NMR (DMSO) δ 11.975 (br s, 1H), 8.416 (d, J=8.4 Hz, 1H), 8.205(br s, 1H), 8.012 (d, J=8 Hz, 1H), 7.423 (s, 2H), 7.376 (d, J=8 Hz, 1H),7.332 (d, J=8 Hz, 1H), 2.512 (s, 3H). MS (M−H) 615. Anal. calcd.: 40.79%C, 1.79% H, 4.53% N; found: 41.05% C, 1.86% H, 4.57% N.

Example 78.3

[0401]¹H NMR (DMSO) δ 11.748 (s, 1H), 8.233 (s, 1H), 7.880 (s, 1H),7.407 (s, 2H), 7.370 (d, J=8 HZ, 1H), 7.330 (d, J=8 Hz, 1H), 2.408 (s,3H). MS (M−H) 595. Anal. calcd.: 42.12% C, 2.19% H, 4.68% N; found:41.84% C, 2.23% H, 4.51% N.

Example 78.4

[0402]¹H NMR (DMSO) δ 11.73 (1H, s), 8.38 (1H, d, J=8.3 Hz), 8.19 (1H,s), 7.99 (1H, d, J=8.3 Hz), 7.88 (1H, d, J=8.6 Hz), 7.45 (1H, d, J=2.3Hz), 7.23-7.40 (3H, m). MS (M−H) 580.8 (M−H). mp 189.0° C.

Example 78.5

[0403]¹H NMR (DMSO) δ 11.57 (1H, s), 8.17 (1H, d, J=8.6 Hz), 7.92 (1H,d, J=2.1 Hz), 7.78 (1H, d, J=8.5 Hz), 7.69 (1H, dd, J=8.6, 2.1 Hz), 7.43(1H, d, J=2.3 Hz), 7.30-7.38 (2H, m), 7.25 (1H, dd, J=8.6, 2.4 Hz). MS(M−H) 546.9. mp 218.1° C.

Example 78.6

[0404]¹H NMR: δ 8.04 (1H, d, 8.3), 8.18 (1H, s), 7.99 (1H, d, 8.3), 7.80(1H, t, 8.3), 7.30-7.40 (2H, m), 7.10-7.22 (2H, m). MS (M−H) 565.0. mp221.2° C. Anal. calcd.: C, 44.45, H, 2.13, N, 4.94; found C, 44.01, H,2.18, N, 4.67.

Example 78.7

[0405]¹H NMR (DMSO) δ 11.60 (1H, s), 8.18 (1H, d, 8.6), 7.91 (1H, d,2.0), 7.79 (1H, t, 8.4), 7.69 (1H, dd, 8.6, 2.1), 7.30-7.40 (2H, m),7.10-7.20 (2H, m). MS (M−H) 530.9. mp 230.4° C. Anal. calcd.: C, 44.99,H, 2.27, N, 5.25; found C, 44.49, H, 2.26, N 5.08.

Example 79

[0406] This example illustrates the preparation of compounds 79.1 to79.7.

[0407] To a solution of 5-chloro-2-mercaptobenzothiazole (Acros) (2 g),KOH (630 mg) in water (8 mL) at 100° C. was added a solution of3,4-dichloronitrobenzene (1.88 g) in n-propanol (24 mL). The mixture washeated at reflux for 72 hrs. After cooling, the solids were collected byfiltration and rinsed with water. The solids were dried under vacuum toafford the nitro derivative 79.1 (2.25 g) as a yellow solid useddirectly in the next step.

[0408]¹H NMR (DMSO) δ 8.54 (d, J=2.4 Hz, 1H), 8.26 (dd, J=8.6, 2.4 Hz,1H), 8.123 (d, J=8.6 Hz, 1H), 8.08 (d, J=1.9 Hz, 1H), 8.03 (d, J=8.7 Hz,1H), 7.533 (dd, J=8.6, 2.1).

[0409] Reduction of 79.1 (2.2 g) with tin dichloride by the method ofexample 32 gave after work-up the aniline (79.2) (1.2 g) which was useddirectly in later reactions.

[0410]¹H NMR (DMSO) δ 7.94 (d, J=8.4 Hz, 1H), 7.891 (d, J=1.6 Hz, 1H),7.537 (d, J=8.4 Hz, 1H), 7.371 (dd, J=8.4, 2.1 Hz, 1H), 6.877 (d, J=2.4Hz, 1H), 6.651 (dd, J=8.4, 2.4 Hz, 1H), 6.203 (s, 2H). MS (M+H) 327.

[0411] Treatment of the aniline 79.2 by the method of example 3 withvarious sulfonyl chlorides gave the sulfonamides of Table 13. TABLE 13

Ra Rb Rc Rd m/e (M − H) 79.3 Cl H Cl Me 547 79.4 Cl H Cl H 533 (M + H)79.5 Cl H CF₃ H 567 79.6 H Cl Cl H 533 79.7 Me H Cl Me 527

Example 79.3

[0412]¹H NMR(DMSO) δ 11.52 (1H, s), 8.20 (1H, s), 7.84-8.00 (4H, m),7.35-7.43 (2H, m), 7.22 (1H, d, J=8.5 Hz), 2.41 (3H, s). MS (M−H) 546.8.mp 203.7° C.

Example 79.4

[0413]¹H NMR(DMSO) δ 11.57 (1H, s), 8.18 (1H, d, J=8.5 Hz), 7.90-7.98(2H, m), 7.86 (1H, d, J=8.5 Hz), 7.72 (1H, d, J=8.7 Hz), 7.37-7.43 (2H,m), 7.22(1H, d, J=8.8 Hz). MS (M+H) 532.8. mp 174.7° C.

Example 79.5

[0414]¹H NMR(DMSO) δ 8.38 (1H, d, 8.4 Hz), 8.21 (1H, s), 8.01 (1H, d,J=8.2 Hz), 7.90-7.96 (2H, m), 7.86 (1H, d, J=7.7 Hz), 7.42 (2H, s), 7.23(1H, d, J=8.6 Hz). MS (M−H) 566.9. mp 158.8° C.

Example 79.6

[0415]¹H NMR(DMSO) δ 11.25 (1H, s), 8.06 (1H, d, J=1.5 Hz), 7.80-7.96(5H, m), 7.40-7.46 (2H, m), 7.27-7.32 (1H, m). MS (M−H) 532.8. mp 201.2°C.

Example 79.7

[0416]¹H NMR(DMSO) δ 11.30 (1H, s), 8.00 (1H, s), 7.90-7.98 (2H, m),7.84 (1H, d, J=8.6 Hz), 7.57 (1H, s), 7.35-7.44 (2H, m), 7.18-7.23 (1H,m), 2.57 (3H, s), 2.37 (3H, s). mp 205.1° C. TABLE 14

Ra Rb Rc Rd m/e (M − H) 79.3 Cl H Cl Me 547 79.4 Cl H Cl H 533 (M + H)79.5 Cl H CF₃ H 567 79.6 H Cl Cl H 533 79.7 Me H Cl Me 527 79.8 Cl H MeH 513 79.9 Cl H t-Bu H 555

Example 79.8

[0417]¹H NMR (d₆-DMSO) δ 11.43 (1H, s), 8.08 (1H, d, J=8.0 Hz),7.90-8.00 (2H, m), 7.85 (1H, d, J=8.5 Hz), 7.57 (1H, s), 7.37-7.47 (3H,m), 7.21 (1H, d, J=8.4 Hz), 2.38 (3H, s). MS (M−H) 512.9. mp 201.0° C.Anal. calcd.; C, 46.56, H, 2.54, N, 5.43; found C, 46.93, H, 2.58, N,5.40.

Example 79.9

[0418]¹H NMR (d₆-DMSO) δ 11.44 (1H, s), 8.10 (1H, d, J=8.3 Hz),7.90-7.97 (2H, m), 7.86 (1H, d, J=8.6 Hz), 7.60-7.68 (2H, m), 7.37-7.43(2H, m), 7.23 (1H, dd, J=8.5,2.4 Hz), 1.29 (9H, s). MS (M−H) 554.9. mp177.8° C. Anal. calcd.; C, 49.51, H, 3.43, N 5.02; found C, 49.67, H,3.44, N, 4.97.

Example 80

[0419] This illustrates the synthesis of compound 80.4.

[0420] 2,6-dimethyl-4-nitro-phenol (4.93 g, 29.5 mmol) was suspended inanhydrous CH₂Cl₂ (30 mL). Hünig's base (12.4 mL, 70 mmol) was added togive a homogeneous, dark red solution. The reaction mixture was cooledto −15° C. and triflic anhydride (10 g, 35 mmol) was slowly added. Thevery dark reaction mixture was stirred at −15° C. for 15 minutes, thenpoured into 3N HCl (100 mL). The layers were separated and the aqueouslayer was extracted 1×150 mL CH₂Cl₂. The combined organic layers werewashed 1×50 mL sat. brine, dried over MgSO₄, and concentrated to a darkred oil. This oil was filtered through a 2 cm plug of silica gel(eluting with 3:1 hexanes:ethyl acetate) and concentrated to an orangeoil which was diluted with 10 mL of hexanes and allowed to stand at roomtemperature until crystallization of the product took place. Thecrystals were collected and dried under vacuum. The mother liquor wasconcentrated, then diluted with 5 mL of CH₂Cl₂ and 25 mL of hexanes andagain allowed to stand until crystallization was complete. The secondcrop was collected by filtration and dried under vacuum. Combined yieldof the two crops was 7.87 g of triflate 80.1.

[0421]¹H NMR (CDCl₃) δ 8.03 (s, 2H); 2.50 (s, 6H).

[0422] 5-methyl-2-mercaptobenzothiazole (1.45 g, 8 mmol) was suspendedin anhydrous THF (3.5 mL). A solution of potassium tert-butoxide (7.35mL, 1.0 N in THF) was added in one portion. The very thick precipitateof the mercaptobenzothiazole potassium salt was dissolved by addition ofDMF (1 mL). Triflate 80.1 (2 g, 6.7 mmol) was dissolved in DMF (1 mL)and added to the reaction mixture which was then heated to 50° C. for 16h. The reaction mixture was pouted into 100 mL DI water and extracted2×50 mL of ethyl acetate. The combined organic layers were washed withsat. brine, dried over MgSO₄, filtered, concentrated, and the residuepurified by flash chromatography (silica gel, 19:1 to 4:1 hexanes:ethylacetate). Fractions containing the desired product were concentrated andthe residue recrystallized from hot hexanes:ethyl acetetate. Filtrationand drying provided the S-arylated compound 80.2 as bright yellowcrystals (0.90 g).

[0423]¹H NMR (CD₃CN) δ 8.12 (s, 2H); 7.68 (d, 1H); 7.61 (s, 1H); 7.17(d, 1H); 2.60 (s, 6H); 2.42 (s, 3H). MS (M+H) 331.1.

[0424] Reduction of 80.2 (0.88 g) by the method of Example 32 gaveaniline 80.3 (0.4 g) as a solid.

[0425]¹H NMR (CDCl₃) δ 7.723 (m, 1H), 7.598 (s, 1H), 7.122 (d, J=8.4 Hz,1H), 6.706 (s, 2H), 5.304 (br, 2H), 2.399 (s, 3H), 2.338 (s, 6H).

[0426] Sulfonylation of 80.3 (400 mg) by the method of example 3 gave80.4 (Table 15)(0.36 g).

[0427]¹H NMR (DMSO) δ 11.284 (s, 1H), 8.369 (d, J=8.2 Hz, 1H), 8.170 (s,1H), 7.969 (d, J=8.2 Hz, 1H), 7.676 (d, J=8.2 Hz, 1H), 7.591 (s, 1H),7.126 (d, J=8.2 Hz, 1H), 7.056 (s, 2H), 2.372 (s, 3H), 2.326 (s, 6H). MS(M+H) 543.

Example 81

[0428] This illustrates the synthesis of compound 81.4.

[0429] 2-chloro-6-methyl-4-nitro-phenol (2.5 g, 13.3 mmol) was convertedto triflate 81.1 according to the method given in Example 80. Triflate81.1 was an oil and could not be recrystallized. 4.0 g of triflate 81.1was obtained.

[0430]¹H NMR (CD₃CN) δ 8.24 (d, 1H); 8.77 (d, 1H); 2.56 (s, 3H).

[0431] 5-methyl-2-mercaptobenzothiazole (1.36 g, 7.5 mmol) and triflate81.1 (2 g, 6.26 mmol) were reacted according to the procedure given inExample 80. S-arylated compound 81.2 was obtained as bright yellowcrystals (1.2 g). This product contained a minor amount of a contaminantof unknown structure. This contaminant had no effect on subsequentreactions, nor was it found in subsequent products.

[0432]¹H NMR (CD₃CN) δ 8.28 (d, 1H); 8.14 (d, 1H); 7.67 (s, 1H); 7.56(d, 1H); 7.14 (d, 1H); 2.68 (s, 3H); 2.45 (s, 3H). MS (M+H) 351.

[0433] Reduction of 81.2 (0.88 g) by the method of Example 32 gaveaniline 81.3 (0.4 g) as a solid.

[0434]¹H NMR (DMSO) δ 7.740 (d, J=8 Hz, 1H), 7.608 (s, 1H), 7.131 (d,J=8 Hz, 1H), 6.732 (d, J=2.6 Hz, 1H), 6.588 (d, J=2.6 Hz, 1H), 6.048 (s,2H), 2.403 (s, 3H), 2.334 (s, 3H).

[0435] Sulfonylation of 81.3 by the method of example 3 gave 81.4 (seeTable 15).

[0436]¹H NMR (DMSO) δ 11.610 (s, 1H), 8.398 (d, J=8.4 Hz, 1H), 8.210 (s,1H), 8.005 (d, J=8.4 Hz, 1H), 7.730 (d, J=8 Hz 1H), 7.621 (s, 1H),7.7.276 (d, J=2.8 Hz, 1H), 7.167 (m, 2H), 2.409 (s, 3H), 2.397 (s, 3H).

Example 82

[0437] This illustrates the synthesis of compound 82.3.

[0438] 5-chloro-2-mercaptobenzothiazole (202 mg, 1 mmol) and triflate80.1 (270 mg, 0.9 mmol) were reacted according to the procedure given inExample 80. S-arylated compound 82.1 was obtained as a light yellowsolid (203 mg).

[0439]¹H NMR (CDCl₃) δ 8.09 (s, 2H); 7.83 (d, 1H); 7.56 (d, 1H); 7.26(dd, 1H); 2.63 (s, 3H). MS (M+H) 351.0.

[0440] Reduction of 82.1 (0.7 g) by the method of example 32 gaveaniline 82.2 (0.62 g).

[0441]¹H NMR (DMSO) δ 7.884 (d, J=8.4 Hz, 1H), 7.846 (d, J=2 Hz, 1H),7.329 (dd, J=8.4, 2 Hz, 1H), 6.495 (s, 2H), 5.669 (s, 2H), 2.283 (s,3H). MS (M+H) 321.

[0442] Sulfonylation of 82.2 by the method of example 3 gave 82.3 (seeTable 15).

[0443]¹H NMR (DMSO) δ 11.304 (s, 1H), 8.377 (d, J=8 Hz, 1H), 8.180 (d,J=1.2 Hz, 1H), 7.980 (br d, J=8.4, 1H), 7.874 (d, J=2.4 Hz, 1H), 7.866(d, J=8 Hz, 1H), 7.365 (dd, J=8.4, 2 Hz, 1H), 7.068 (br s, 2H), 2.341(s, 3H). MS (M−H) 561.

Example 83

[0444] This illustrates the synthesis of compound 83.3.

[0445] 5-chloro-2-mercaptobenzothiazole (0.76 g, 3.75 mmol) and triflate81.1 (1.0 g, 3.44 mmol) were reacted according to the procedure given inExample 80. S-arylated compound 83.1 was obtained as a light yellowsolid (0.83 g).

[0446]¹H NMR (CDCl₃) δ 8.30 (s, 1H); 8.17 (s, 1H); 7.85 (s, 1H); 7.61(d, 1H); 7.30 (d, 1H); 2.71 (s, 3H). MS (M+H) 371.

[0447] Reduction of 83.1 (0.8 g) by the method of Example 32 gaveaniline 83.2 (0.47 g).

[0448]¹H NMR (DMSO) δ 7.918 (d, J=8.8 Hz, 1H), 7.874 (d, J=2 Hz, 1H),7.356 (dd, J=8.4, 2 Hz, 1H), 6.745 (d, J=2.4 Hz, 1H), 6.600 (d, J=2 Hz,1H), 6.089 (br s, 2H), 2.336 (s, 3H). MS (M+H) 341.

[0449] Sulfonylation of 83.2 by the method of example 3 gave 83.3 (seeTable 15).

[0450]¹H NMR (DMSO) δ 11.647 (s, 1H), 8.407 (d, J=8.4 Hz, 1H), 8.213 (brs, 1H), 8.008 (br d, J=8.4, 1H), 7.910 (d, J=8 Hz, 1H), 7.90 (s, 1H),7.396 (d, J=8.8 H, 1H), 7.290 (br s, 1H), 7.188 (br s, 1H), 2.416 (s,3H). MS (M−H) 581. TABLE 15

X V W m/e (M − H) 80.4 Me Me Me 543 (M + H) 81.4 Me Me Cl 82.3 Cl Me Me561 83.3 Cl Me Cl 581 84.3 Cl H Me 547

Example 84

[0451] This illustrates the synthesis of compound 84.3

[0452] Sodium hydride (1 g, 60% in oil) was added to a solution of5-chloro-2-mercaptobenzothiazole (5.4 g) in DMF (50 mL). After gasevolution had subsided a solution of 2-chloro-5-nitro toluene in DMF wasadded and the mixture heated at 60° C. for 2 days. After cooling, thesolution was filtered. The filtrate was diluted with water and extractedinto ethyl ether. The organic layer was concentrated to a brown oilwhich was treated with hexane to form a solid precipitate which wascollected by filtration as 84.1 (0.624 g).

[0453]¹H NMR (DMSO) δ 8.372 (d, J=2.4 Hz, 1H), 8.171 (dd, J=8.8, 2.4 Hz,1H), 8.027 (d, J=8.8 Hz, 1H), 8.003 (d, J=8 Hz, 1H), 7.988 (d, J=2 Hx,1H), 7.454 (dd, J=8.4, 1.6 Hz, 1H), 2.553 (s, 3H).

[0454] Reduction of 84.1 (0.6 g) with SnCl₂ by the method of example 32gave after chromatography 84.2 (0.48 g) as a solid.

[0455]¹H NMR (DMSO) δ 7.899 (d, J=8.8 Hz, 1H), 7.853 (d, J=2 Hz, 1H),7.345 (d, J=8.4 Hz, 1H), 7.336 (dd, J=8.4, 2 Hz, 1H), 6.631 (d, J=2 Hz,1H), 6.531 (dd, J=8.4, 2 Hz, 1H), 5.766 (br s, 2H). MS (M+Na) 329.

[0456] Sulfonylation of 84.2 (0.4 g) by the method of example 3 gave84.3 (Table 15) (0.66 g) as a foam.

[0457]¹H NMR (DMSO) δ 11.376 (s, 1H), 8.355 (d, J=8 Hz, 1H), 8.180 (d,J=1.2 Hz, 1H), 7.983 (dd, J=8.4, 2 Hz, 1H), 7.893 (d, J=9.2 Hz, 1H),7.88 (s, 1H), 7.656 (d, J=8.4 H, 1H), 7.377 (dd, J=8.8, 1.6 Hz, 1H),7.211 (d, J=2.8 Hz, 1H), 7.108 (dd, J=8.4, 2 Hz, 1H), 2.334 (s, 3H). MS(M−H) 547.

Example 85

[0458] This illustrates the synthesis of compound 85.3

[0459] Compound 85.1 was prepared by a modification of the publishedprocedure of Albert and Barlin (J. Chem. Soc. 2384-2396 (1959).3-Aminoquinoline (15.0 g, 105 mmol) was suspended in a mixture of 10NHCl (40 mL), ice (21 g) and water (100 mL) at 0-5° C., before sodiumnitrite (7.6 g, 110 mmol) was added slowly. The mixture was then addedportionwise to another solution of potassium ethyl xanthate_(20.8 g, 125mmol) in water (60 mL) at 45° C. The mixture was heated for 1 hr beforecooling off. The mixture was then extracted with ether. The etherealsolution was washed with 2N NaOH solution, water, and brine beforedrying over magnesium sulfate. After filtration, the removal of thesolvent gave a brown oil (15 g), which was then dissolved in ethanol(150 mL) and refluxed with KOH (25 g) under nitrogen overnight. Theethanol solvent was then removed under vacuum, and the residue wasseparated between water and ether. The ethereal solution was discarded.The aqueous solution was acidified to pH=˜4, before it was extractedwith ether. Then ethereal solution was washed with brine, dried overmagnesium sulfate, filtered and concentrated under vacuum to give crudeproduct (7.5 g) as a brown oil. Subsequent flash chromatography witheluent (0%-5%-10% ethyl acetate/dichloromethane) produced3-mercaptoquinoline (85.1) (5.35 g, 32% yield) as a solid.

[0460]¹H NMR (DMSO) δ 9.02 (1H, d, J=2.3 Hz), 8.63 (1H, d, J=2.2 Hz),7.95-8.05 (2H, m), 7.75-8.02 (1H, m), 7.60-7.67 (1H, m).

[0461] To a mixture of 3-mercaptoquinoline (85.1)(1.18 g, 7.33 mmol) and1,2,3-chloro-5-nitrobenzene (1.66 g, 7.33 mmol) dissolved in ethanol(100 mL), was added a THF solution of t-BuOK (7.5 mL, 1M). The mixturewas then heated at 80° C. overnight before cooling off. After theremoval of ethanol solvent, the mixture was separated between ethylacetate and water. The organic solution was washed with brine, driedover magnesium sulfate and filtered. The filtrate was then concentratedto give a crude product, which was then flash chromatographed witheluent (10% hexanes/dichloromethane) to afford 85.2 (1.80 g, 70% yield)as a yellow oil.

[0462]¹H NMR (DMSO) δ 8.75 (1H, d, J=2.3), 8.51 (1H, s), 8.22 (1H, s),8.01 (1H, d, J=8.4 Hz), 7.92 (1H, d, J=7.6 Hz), 7.74-7.80 (1H, m),7.60-7.66 (1H, m).

[0463] An ethyl acetate solution (100 mL) of 85.2 (1.80 g, 5.1 mmol) andtin chloride (II) dihydrate (6.88 g, 30 mmol) was heated at refluxovernight before cooling off. The solution was then poured into 1N NaOHsolution (400 mL). After stirring for 30 min, the mixture was separated,and the organic solution was washed with water, saturated sodiumbicarbonate and brine. After drying over magnesium sulfate, the solutionwas filtered and concentrated under vacuum. The residue was mixed withdichloromethane (10 mL) and sonicated. Subsequent vacuum filtrationprovided the aniline 85.3 (1.35 g, 82% yield) as an off-white solid.

[0464]¹H NMR (DMSO) δ 8.61 (1H, d, J=2.4), 7.96 (1H, d, J=8.4 Hz), 7.88(1H, d, J=8.2 Hz), 7.83 (1H, d, J=2.2 Hz), 7.67-7.72 (1H, m), 7.54-7.60(1H, m). mp 213.2° C.

Example 86

[0465] This illustrates the synthesis of compound 86 (see Table 16).

[0466] The aniline 85.3 (250 mg, 0.78 mmol) and 2-chlorobenzenesufonylchloride (339 mg, 1.60 mmol) were dissolved in a mixed solvent of THF (5mL) and dichloromethane (5 mL). To the solution was added pyridine(0.185 mL, 2.34 mmol) and catalytic amount of DMAP. The solution washeated at 50° C. to distill off dichloromethane, and then THF withassistance of vacuum. The residue was flash chromatographed with eluent(2.5% ethyl acetate/dichloromethane) to give sulfonamide 86 (302 mg, 78%) as an off-white solid.

[0467]¹H NMR(DMSO) δ 11.58 (1H, s), 8.61 (1H, d, J=2.4 Hz), 8.19 (1H, d,J=7.6 Hz), 7.83-8.00 (3H, m), 7.67-7.75 (3H, m), 7.56-7.65 (2H, m), 7.31(2H, s). MS (M+H) 494.9. mp: 219.6° C. Anal. calcd: C, 50.87, H, 2.64,N, 5.65; found C, 50.86, H 2.62, N, 5.52.

[0468] The compounds of Table 16 were prepared by the method of example86 from compound 84.3 and the corresponding arylsulfonyl chloride. TABLE16

k R_(a) R_(b) R_(c) R_(d) m/e (M + H) 86 0 Cl H H H 495 87.1 0 Cl H Cl H529 87.2 0 H H H H 461 87.3 0 Cl H CF₃ H 561 (M − H) 88.1 1 Cl H H H 51188.2 1 Cl H Cl H 543 (M − H) 88.3 1 H H H H 477

Example 87 Example 87.1

[0469]¹H NMR(DMSO) δ 11.66 (1H, broad), 8.63 (1H, d, J=2.3 Hz), 8.18(1H, d, J=8.6 Hz), 7.85-8.00 (4H, m), 7.70-7.75 (2H, m), 7.57-7.62 (1H,m), 7.32 (2H, s). MS (M+H) 529.0. mp 214.0° C. Elemental Analysis:theory C, 47.56, H, 2.28, N, 5.28; Found C, 47.30, H, 2.36, N, 5.37.

Example 87.2

[0470]¹H NMR(DMSO): δ 11.22 (1H, s), 8.61 (1H, d, J=2.3 Hz), 7.82-7.98(5H, m), 7.57-7.75 (5H, m), 7.34 (2H, s). MS (M+H) 461.0. mp 246.8° C.Elemental Analysis theory C, 54.67, H, 3.06, N, 6.07; found C, 54.71, H,3.05, N, 5.94.

Example 87.3

[0471]¹H NMR (DMSO) δ 11.70-12.00 (1H, broad), 8.60-8.67 (1H, m),8.35-8.43 (1H, m), 8.20-8.25 (1H, m), 7.56-8.06 (6H, m), 7.32-7.38 (2H,m). MS (M−H) 560.9. mp: 225.1° C. Elemental Analysis: theory C, 46.86,H, 2.15, N, 4.97; found C. 47.01, H, 2.26, N, 4.98.

Example 88

[0472] General procedure for sulfur oxidation to the sulfoxide:

[0473] A naphthylthioether of examples 86 or 87 (0.2 mmol) was dissolvedin a mixed solvent of dichloromethane (10 mL) and methanol (5 mL). Tothe solution was added mCPBA (120 mg, 0.7 mmol, 77% pure) in six batchesover 20 minute intervals. Then the solution was washed with 5% sodiumthiosulfate solution, 1% sodium bicarbonate solution and brine and thendried over magnesium sulfate. After filtering, the filtrate wasconcentrated to give a crude product, which was then flashchromatographed with eluent (5% -30% ethyl acetate/dichloromethane) toafford the corresponding sulfoxide.

Example 88.1

[0474]¹H NMR (DMSO): δ 11.75 (1H, s), 8.82 (1H, s), 8.68 (1H, s),8.15-8.20 (2H, m), 8.09 (1H, d, J=8.5 Hz), 7.85-7.91 (1H, m), 7.67-7.75(3H, m), 7.57-7.64 (1H, m), 7.17 (2H, s). MS (M+H) 511. mp 239.5° C.with decomposition. Elemental Analysis: theory C, 49.28, H, 2.56, N,5.47; found C, 49.30, H, 2.63, N, 5.37.

Example 88.2

[0475]¹H NMR(DMSO): δ 11.5-12.0 (broad), 8.83 (1H, s), 8.68 (1H, s),8.15-8.20 (2H, m), 8.09 (1H, d, J=8.5 Hz), 7.85-7.92 (2H, m), 7.55-7.75(2H, m), 7.17 (2H, s). MS (M−H) 542.9. mp: 234.4. Elemental Analysis:theory C, 46.17, H, 2.21, N, 5.13; found C, 45.97, H, 2.26, N, 4.92.

Example 88.3

[0476]¹H NMR(DMSO) δ 11.43 (1H, s), 8.81 (1H, s), 8.68(1H, s), 8.18(1H,d, J=8.2 Hz), 8.09 (1H, d, J=8.5 Hz), 7.82-7.90 (3H, m), 7.58-7.74 (4H,m), 7.21 (2H, s). MS (M+H) 476.9. mp 261.8° C. with decomposition.Elemental Analysis: theory C 52.83, H, 2.96, N, 5.87; found C, 52.71, H,3.05, N, 5.71.

Example 89

[0477]

[0478] 2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-napthalene (89)

[0479] 2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-napthalene wassynthesized (100% ) from 3,4,5-trichloronitrobenzene (Acros) andnapthalene-2-thiol (Avocado) in a similar manner as described in example1 using DMSO as solvent instead of DMF.

[0480]¹H NMR (DMSO-d₆) δ 8.48 (s, 2H), 7.95-7.85 (m, 1H), 7.88 (d, J=8.6Hz, 1H), 7.85-7.8 (m, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.55-7.45 (m, 2H),7.25 (dd, J=8.7, 2.0 Hz, 1H).

Example 90

[0481]

[0482] 3,5-dichloro-4-(napthalen-2-ylsulfanyl)-phenylamine (90)

[0483] To a 0.1M solution2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-napthalene (89) (774 mg, 2.2mmol), in EtOAc was added tin(II)chloride dihydrate, obtained fromAldrich, (2.49 g, 11.05 mmol). The resulting mixture was refluxed for 2hour. The crude reaction mixture was cooled to ambient temperature andexcess 2M aqueous NaOH was added and allowed to stir for 15 minutes.Solid tin salts precipitated from the solution, were filtered offthrough a pad of celite and washed with EtOAc (200 mL). The organiclayer was washed twice with brine (200 mL), dried over Na₂SO₄, andconcentrated under vacuum to yield 592 mg (84% ) of (90) which was usedwithout further purification.

[0484]¹H NMR (DMSO-d₆) δ 7.88-7.82 (m, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.75(d, J=7.7 Hz, 1H), 7.5-7.4 (m, 3H), 7.13 (dd, J=8.7, 1.9 Hz, 1H), 6.83(s, 2H), 6.21 (s, 2H). MS (M−H) 318.

Example 91

[0485]

[0486] 2-(2-Chloro-4-nitro-phenylsulfanyl)-napthalene (91)

[0487] 2-(2-Chloro-4-nitro-phenylsulfanyl)-napthalene was synthesized(100% ) from 3-chloro-4-fluoro-nitrobenzene (Aldrich) andnapthalene-2-thiol (Avocado) in a similar manner as described in example89.

[0488]¹H NMR (DMSO-d₆) δ 8.4-8.34 (m, 2H), 8.14 (d, J=8.6 Hz, 1H),8.09-8.0 (m, 3H), 7.72-7.6 (m, 3H), 6.88 (d, J=8.9 Hz, 1H).

Example 92

[0489]

[0490] 3-chloro-4-(napthalen-2-ylsulfanyl)-phenylamine

[0491] 3-chloro-4-(napthalen-2-ylsulfanyl)-phenylamine (92) wassynthesized (97% ) from 2-(2-Chloro-4-nitro-phenylsulfanyl)-napthalene(91) in a similar manner as described in example 90.

[0492]¹H NMR (DMSO-d₆) δ 7.88-7.8 (m, 2H), 7.75 (d, J=7.5 Hz, 1H),7.5-7.42 (m, 3H), 7.35 (d, J=8.4 Hz, 1H), 7.18 (dd, J=8.6, 1.8 Hz, 1H),6.82 (d, J=2.4 Hz, 1H), 6.6 (dd, J=8.4, 2.4 Hz, 1H). MS (M+H) 286.

Example 93

[0493]

[0494]2,4-Dichloro-N-[3,5-dichloro-4-(napthalen-2-ylsulfanyl)-phenyl]-benzenesulfonamide(93)

[0495] To a 0.4M solution of3,5-dichloro-4-(napthalen-2-ylsulfanyl)-phenylamine (90)(153 mg, 0.48mmol ) in THF was added pyridine, obtained from aldrich, (0.19 mL, 2.4mmol) followed by 2,4-dichlorobenzenesulfonyl chloride, obtained fromMaybridge, (129 mg, 0.53 mmol). The resulting mixture was stirred for 6days. A 1M aqueous solution of HCl (20 mL) was added and the crudereaction mixture was extracted 3× with EtOAc (20 mL). The organic layerswere combined and washed once with a brine solution (20 mL), dried overNa₂SO₄, and concentrated under vacuum. The crude solid waschromatographed (5-15% EtOAc in hexane) to yield 125 mg (49% ) of 93 asan off white solid.

[0496]¹H NMR (DMSO-d₆) δ 11.6 (s, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.96 (d,J=2.1 Hz, 1H), 7.88-7.83 (m, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.76-7.73 (m,1H), 7.1 (dd, J=8.6, 2.1 Hz, 1H), 7.52-7.44 (m, 3H), 7.32 (s, 2H), 7.21(s, 2H), 7.1 (dd, J=8.6, 2.0 Hz, 1H). MS (M−H) 526.

Example 94

[0497]

[0498] 6-Chloro-pyridine-3-sulfonic acid[3-chloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-amide (94).

[0499] To a 0.35M solution of3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90)(150 mg, 0.53 mmol)in THF was added pyridine (Aldrich, 0.21 mL, 2.63 mmol) followed by6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 122 mg, 0.58 mmol). Theresulting mixture was stirred for 15 hours. A 1M aqueous solution of HCl(20 mL) was added and the crude reaction mixture was extracted 3× withEtOAc (50 mL). The organic layers were combined and washed twice with abrine solution (100 mL), dried over Na₂SO₄, and concentrated undervacuum. The crude solid was chromatographed (5-15% EtOAc in hexane) toyield 140 mg (58% ) of 94 as a pale yellow solid.

[0500]¹H NMR (DMSO-d₆) δ 10.93 (s, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.19(dd, J=8.4, 2.6 Hz, 1H), 7.97-7.90 (m, 2H), 7.90-7.84 (m, 2H), 7.78 (d,J=8.4 Hz, 1H), 7.59-7.52 (m, 2H), 7.36 (dd, J=8.6, 1.9 Hz, 1H), 7.29 (d,J=2.1 Hz, 1H), 7.12-7.04 (m, 2H). MS (M−H).

Example 95

[0501]

[0502]2-Chloro-N-[3-chloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(95)

[0503] The title compound was prepared using the method of example 94,starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (150 mg,0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge, 162 mg,0.58 mmol) in THF. 250 mg (90% ) of title compound (95) was obtained asa pale yellow solid.

[0504]¹H NMR (DMSO-d₆) δ 11.30 (s, 1H), 8.23 (d, J=8.3 Hz, 1H), 8.18 (d,J=1.6 Hz, 1H), 7.97-7.84 (m, 3H), 7.84-7.80 (m, 2H), 7.58-7.50 (mn, 2H),7.32 (dd, J=8.6, 1.9 Hz, 1H), 7.28 (d, J=2.3 Hz, 1H), 7.11 (d, J=8.6 Hz,1H), 7.04 (dd, J=8.6, 2.3 Hz, 1H). MS (M−H) 526.

Example 96

[0505]

[0506] 6-Chloro-pyridine-3-sulfonic acid[3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-amide (96)

[0507] The title compound was prepared using the method of example 94,starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90)(150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 109 mg, 0.52 mmol) inTHF. 130 mg (56% ) of 96 was obtained as a pale yellow solid.

[0508]¹H NMR (DMSO-d₆) δ 11.40 (br s, 1H), 8.88 (d, J=1.9 Hz, 1H), 8.28(dd, J=8.4,1.6 Hz, 1H), 7.88-7.80 (m, 3H), 7.76 (d, J=9.1, 1.8 Hz, 1H),7.52-7.42 (m, 3H), 7.38 (s, 2H), 7.14 (dd, J=8.7, 2.0 Hz, 1H). MS (M−H)493.

Example 97

[0509]

[0510]2-Chloro-N-[3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(97)

[0511] The title compound was prepared using the method of example 94,starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine(90)(150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge, 144 mg,0.52 mmol) in THF. 137 mg (52% ) of 97 was obtained as a pale yellowsolid.

[0512]¹H NMR (DMSO-d₆) δ 8.38 (d, J=8.0 Hz, 1H), 8.21 (d, J=1.4 Hz, 1H),8.01 (dd, J=8.4, 1.1 Hz, 1H), 7.88-7.80 (m, 2H), 7.76-7.71 (m, 1H),7.51-7.42 (m, 2H), 7.34 (s, 2H), 7.12 (dd, J=8.6, 2.0 Hz, 1H). MS (M−H)560.

Example 98

[0513]

[0514] 6Chloro-imidazo[2,1-b]thiazole-5-sulfonic acid[3-chloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-amide (98)

[0515] The title compound was prepared using the method of example 94,starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (92) (150mg, 0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (Maybridge, 149 mg,0.58 mmol) in THF. 172 mg (65% ) of 98 was obtained as a pale yellowsolid.

[0516]¹H NMR (DMSO-d₆) δ 11.26 (s, 1H), 7.98 (d, J=4.4 Hz, 1H),7.96-7.88 (m, 2H), 7.88-7.84 (m, 2H), 7.68 (d, J=2.4 Hz, 1H), 7.58-7.52(m, 2H), 7.33-7.28 (m, 2H), 7.14 (d, J=8.5 Hz, 1H), 7.01 (dd, J=8.5, 2.4Hz, 1H), 7.04 (dd, J=8.6, 2.3 Hz, 1H). MS (M−H) 504.

Example 99

[0517]

[0518]2,4-Dichloro-N-[3-chloro-4-(napthalen-2-ylsulfanyl)-phenyl]-benzenesulfonamide(99)

[0519]2,4-Dichloro-N-[3-chloro-4-(napthalen-2-ylsulfanyl)-phenyl]-benzenesulfonamide was synthesized (67% ) from3-chloro-4-(napthalen-2-ylsulfanyl)-phenylamine (92) and2,4-dichlorobenzenesulfonyl chloride, obtained from Maybridge, in asimilar manner as described in example 93.

[0520]¹H NMR (DMSO-d₆) δ 11.1 (s, 1H), 8.06 (d, J=8.6 Hz, 1H),7.95-7.88(m, 3H), 7.86-7.81 (m, 2H), 7.65 (dd, J=8.4 Hz, 1H), 7.57-7.51(m, 2H), 7.31 (dd, J=8.6, 1.9 Hz, 1H), 7.26 (d, J=2.2 Hz, 1H), 7.12 (d,J=8.7 Hz, 1H), 7.03 (dd, J=8.6, 2.3 Hz, 1H). MS (M−H) 492.

Example 100

[0521]

[0522]N-[3-Chloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-4-iodo-benzenesulfonamide(100)

[0523] The title compound was prepared using the method of example 94,starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (92)(150mg, 0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and4-iodobenzenesulfonyl chloride (Acros, 175 mg, 0.58 mmol) in THF. 153 mg(53% ) of 100 was obtained as a pale yellow solid.

[0524]¹H NMR (DMSO-d₆) δ 10.75 (s, 1H), 8.01-7.95 (m, 2H), 7.95-7.89 (m,2H), 7.87-7.82 (m, 2H), 7.59-7.50 (m, 4H), 7.32 (dd, J=8.6, 1.9 Hz, 1H),7.26 (d, J=2.3 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 7.04 (dd, J=8.5, 2.2 Hz,1H). MS (M−H) 550.

Example 101

[0525]

[0526]N-[3,5-Dichloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-4-iodo-benzenesulfonamide(101)

[0527] The title compound was prepared using the method of example 94,starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90)(150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and4-iodobenzenesulfonyl chloride (Acros, 155 mg, 0.52 mmol) in THF. 254 mg(93% ) of 101 was obtained as a pale yellow solid.

[0528]¹H NMR (DMSO-d₆) δ 11.22 (s, 1H), 8.08-8.02 (m, 2H), 7.88-7.82 (m,2H), 7.74 (d, J=7.7 Hz, 1H), 7.65-7.58 (m, 2H), 7.52-7.40 (m, 3H), 7.35(s, 2H), 7.12 (dd, J=8.7, 1.9 Hz, 1H). MS (M−H) 584.

Example 102

[0529]

[0530] 6-Chloro-imidazo[2,1-b]thiazole-5-sulfonic acid[3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-amide (102)

[0531] The title compound was prepared using the method of example 94,starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine(90)(150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (Maybridge, 132 mg,0.52 mmol) in THF. 172 mg (65% ) of 102 was obtained as a pale yellowsolid.

[0532]¹H NMR (DMSO-d₆) δ 11.71 (br s, 1H), 8.02 (d, J=4.4 Hz, 1H),7.89-7.82 (m, 2H), 7.77 (m, 1H), 7.72 (d, J=4.4 Hz, 1H), 7.52-7.432 (m,3H), 7.35 (s, 2H), 7.11 (dd, J=8.7, 2.0 Hz, 1H). MS (M−H) 504.

Example 103

[0533]

[0534] 6-Chloro-pyridine3-sulfonic acid[3-chloro4-(naphthalene-2-sulfinyl)-phenyl]-amide (103)

[0535] To a solution of 6-Chloro-pyridine-3-sulfonic acid[3-chloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-amide (94, 55 mg, 0.12mmol) in CH₂Cl₂ (2 mL), was added dropwise a solution ofm-chloroperoxybenzoic acid (mCPBA, Aldrich, 36 mg, 0.12 mmol) in CH₂Cl₂(1 mL). The resulting mixture was stirred at ambient temperature for 1hour and diluted with EtOAc (60 mL). The organic layer was washed withsaturated aqueous NaHCO₃ solution (50 mL), twice with brine solution (50mL), dried over Na₂SO₄, and concentrated under vacuum. The crude solidwas chromatographed (10-25% EtOAc in hexane) to yield 17 mg (30%) of 103as an off white solid.

[0536]¹H NMR (DMSO-d₆) δ 11.25 (s, 1H), 8.82 (d, J=2.6 Hz, 1H), 8.43 (d,J=1.5 Hz, 1H), 8.19 (dd, J=8.4, 2.6 Hz, 1H), 8.10 (m, 1H), 8.04 (d,J=8.5 Hz, 1H), 7.98 (m, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.74 (d, J=8.5 Hz,1 H), 7.70-7.60 (m, 2H), 7.53 (dd, J=8.7, 1.8 Hz, 1H), 7.40 (dd, J=8.5,2.2 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H). MS (M−H) 475.

Example 104

[0537]

[0538] 6-Chloro-pyridine-3-sulfonic acid[3,5-dichloro-4-(naphthalene-2-sulfonyl)-phenyl]-amide (104)

[0539] To a solution of 6-Chloro-pyridine-3-sulfonic acid[3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-amide (96, 20 mg, 0.04mmol) in CH₂Cl₂ (1 mL), was added dropwise a solution of mCPBA (Aldrich,36 mg, 0.12 mmol) in CH₂Cl₂ (1 mL). The resulting mixture was stirred atambient temperature overnight and diluted with EtOAc (60 mL). Theorganic layer was washed twice with 5% aqueous Na2S2O3 solution (20 mL),twice with 1% aqueous NaHCO₃ solution (20 mL), and brine solution (20mL), dried over Na₂SO₄. Removal of the solvent under vacuum gave 21 mg(99%) of 104 as an off white solid.

[0540]¹H NMR (DMSO-d₆) δ 8.68 (d, J=2.5 Hz, 1H), 8.58 (d, J=1.8 Hz, 1H),8.22 (d, J=8.1 Hz, 1H), 8.12-8.05 (m, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.79(dd, J=8,7, 2.20 Hz, 1H), 7.76-7.64 (m, 2H), 7.58 (d, J=8.4 Hz, 1H),6.93 (s, 2H). MS (M−H) 525.

Example 105

[0541]

[0542]2-Chloro-N-[3-chloro-4-(naphthalene-2-sulfonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(105)

[0543] The title compound was prepared using the method of Example 104,starting with2-Chloro-N-[3-chloro-4-(naphthalen-2ylsulfanyl)-phenyl]-4-trifluoromethylbenzene-sulfonamide(95, 35 mg, 0.066 mmol), mCPBA (Aldrich, 100 mg, 0.33 mmol) in CH₂Cl₂.38 mg (100%) of 105 was obtained as an off white solid.

[0544]¹H NMR (DMSO-d₆) δ 11.90 (br s, 1H), 8.62 (d, J=1.8 Hz, 1H), 8.28(d, J=8.1 Hz, 1H), 8.20 (d, J=8.1 Hz 1H), 8.16-8.00 (m, 4H), 7.90 (d,J=8.5 Hz 1H), 7.77-7.64 (m, 3H), 7.20 (d, J=9.0 Hz, 1H), 7.09 (s, 1H).MS (M−H) 558.

Example 106

[0545]

[0546] 6-Chloro-pyridine-3-sulfonic acid[13-chloro-4-(naphthalene-2-sulfonyl)-phenyl]-amide (106)

[0547] The title compound was prepared using the method of Example 104,starting with 6-Chloro-pyridine-3-sulfonic acid[3-chloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-amide (94, 15 mg, 0.03mmol), mCPBA (Aldrich, 50 mg, 0.15 mmol) in CH₂Cl₂. 16 mg (100%) of 106was obtained as an off white solid.

[0548]¹H NMR (DMSO-d₆) δ 11.60 (br s, 1H), 8.82 (d, J=2.5 Hz, 1H), 8.62(d, J=1.8 Hz, 1H), 8.24-8.16 (m, 2H), 8.14 (d, J=8.8 Hz, 1H), 8.08 (d,J=8.8 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.76-7.64 (m, 4H), 7.27 (dd,J=8.8, 2.0 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H). MS (M−H) 491.

Example 107

[0549]

[0550]2-Chloro-N-[3,5-dichloro-4-(naphthalene2-sulfonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(107)

[0551] The title compound was prepared using the method of Example 104,starting with2-Chloro-N-[3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-4-trifluoromethylbenzene-sulfonamide(97, 30 mg, 0.05 mmol), mCPBA (Aldrich, 80 mg, 0.26 mmol) in CH₂Cl₂. 32mg (100%) of 107 was obtained as an off white solid.

[0552]¹H NMR (DMSO-d₆) δ 8.59 (d, J=1.1 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H),8.15 (d, J=8.1 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H),7.90 (s, 1H), 7.84-7.77 (m, 2H), 7.75-7.64 (m, 2H), 6.92 (s, 2H). MS(M−H) 592.

Example 108

[0553] This Example illustrates the preparation of 108.1 through 108.6.

[0554] A solution of potassium t-butoxide (1 M in THF; 26.5 mL) wasadded to a solution of 3,4,5-trichloronitrobenzene (3 g) and5-chloro-3-hydroxypyridine (1.7 g) in THF (15 mL). The deep red solutionwas heated at 50° C. overnight, then poured into water. The precipitatewas collected by filtration and purified by chromatography on silica(10% ethyl acetate/hexanes as eluant) to provide 108.1.

[0555]¹H NMR (400 MHz) (DMSO-d₆) δ 8.58 (s, 2H); 8.47 (d, J=2 Hz, 1H);8.41 (d, J=2.6 Hz, 1H); 7.72 (dd, J=2.6, 2 Hz, 1H).

[0556] Using the method of Example 2, 108.1 (2.2 g) was converted to theaniline 108.2.

[0557]¹H NMR (400 MHz) (DMSO-d₆) δ 8.35 (d, J=2 Hz, 1H); 8.21 (d, J=2.5Hz, 1H); 7.37 (dd, J=2.5, 2 Hz, 1H); 6.73 (s, 2H); 5.78 (br s, 2H).

[0558] The compounds provided in Table 17 were prepared using 108.2 andcommercially available substituted benzenesulfonyl chlorides and/orusing the intermediates and methods described in the examples above.TABLE 17

Ra Rb Rc Rd mp (° C.) 108.3 H Cl Cl H 199-200 108.4 Cl H Cl H 166-169108.5 H H I H 211-214 108.6 Cl H CF₃ H 185-189

Example 109

[0559] This Example illustrates the synthesis of 109.1.

[0560] A round-bottomed flask was charged with 2-chloro-4-nitrobenzoylchloride (3.50 g, 15.9 mmol), 2-ethylbenzofuran (2.11 g, 14.4 mmol), andanhydrous methylene chloride (20 mL). This was cooled in an ice/waterbath and titanium tetrachloride (5.49 g, 28.9 mmol) was added in adropwise fashion with vigorous stirring. After addition was complete,the reaction was stirred at 0° C. for 20 minutes and then was warmed toroom temperature for an additional four hours. The reaction was thendiluted with 80 mL of methylene chloride and washed twice with 50 mLvolumes of 2N HCl and then once with 50 mL of brine. The organics weredried over Na₂SO₄ and concentrated to a yellow oil. This oil was furtherpurified using silica gel flash chromatography (eluting with 20% hexanesin methylene chloride). The desired fractions were concentrated to give2.9 g (61%) of ketone 109.1 as an off-white solid.

[0561] MS ESI m/e: 330.0 (M+H).

Example 110

[0562] (2,6-Dichloro-4-nitro-phenyl)-acetic acid (110)

[0563] To a solution of diethyl malonate (Aldrich, 13.8 mL, 90 mmol) inDMF (60 mL) was added cesium carbonate (Aldrich, 48.9 g, 150 mmol). Themixture was heated to 70° C. and then was added1,2,3-trichloro-5-nitrobenzene (Aldrich, 13.56 g, 60 mmol). The mixturewas stirred at 70° C. for 3 hours and cooled to room temperature. A 2Maqueous solution of HCl (50 mL) was added and the crude reaction mixturewas extracted 3× with EtOAc (150 mL). The organic layers were combinedand washed twice with a brine solution (150 mL), dried over Na₂SO₄, andconcentrated under vacuum. The light yellow oil was used for the nextreaction without further purification.

[0564] The light yellow oil was suspended in 90 mL of 6 N aqueous HCl.The mixture was refluxed overnight (15 hours). The mixture was cooled inthe ice bath for 2 hours and filtered. The crude solid product wastriturated with CH₂Cl₂/Hexanes to give compound 110 (11.5 g, 77%) aspale brown solid.

[0565]¹H NMR (DMSO-d₆) δ 13.00 (br s, 1H), 8.23 (s, 2H), 4.16 (s, 2H).

Example 111

[0566] (2-Chloro-4-nitro-phenyl)-acetic acid (111)

[0567] The title compound was prepared using the method of Example 110,starting with diethyl malonate (Aldrich, 30.5 mL, 200 mmol),3,4-dichloronitrobenzene (Aldrich, 19.2 g, 100 mmol), cesium carbonate(Aldrich, 81.5 g, 250 mmol) and 150 mL of aqueous 6N HCl solution. 18.8g (87%) of compound 111 was obtained as pale yellow solid.

[0568]¹H NMR (DMSO-d₆) δ 12.80 (br s, 1H), 8.29 (d, J=2.4 Hz, 1H), 8.18(dd, J=8.4, 2.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 3.90 (s, 2H).

Example 112

[0569] 2-Amino-4-chloro-benzenethiol hydrochloride (112)

[0570] By the procedure of R. L. Danley and D. A. Zazaris (Can. J. Chem.43, 2610-2612 (1965) sodium tetrasulfide was obtained by dissolvingsulfur (Aldrich, 9.6 g, 300 mmol) in molten sodium sulfide nonahydrate(Aldrich, 24.0 g, 100 mmol). This hot liquid was added to a solution of2,5-dichloronitrobenzene (Aldrich, 38.4 g, 200 mmol) in 95% ethanol (140mL). After the exothermic reaction had ceased, the mixture was refluxedfor 2 hours and filtered while hot. The precipitate was washed withwater (50 mL) and ethanol (50 mL) to give 37.7 g of intermediatetrisulfide as a yellow solid.

[0571]¹H NMR (CDCl₃) δ 8.83 (d, J=2.3 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H),7.55 (dd, J=8.6, 2.3 Hz, 1H).

[0572] Concentrated hydrochloric acid (125 mL) was slowly (overnight, 15hours) added to a well-stirred suspension of the trisulfide (37.7 g)described above and tin (Aldrich, 88 g, 737 mmol) in 95% ethanol (200mL). After filtration of the hot solution, the filtrate was allowed tostand at room temperature overnight to precipitate the crude product.The precipitate was collected by filtration, washed with 1:1ethanol/concentrated HCl. Recrystalization from 1:1 MeOH/concentratedHCl gave compound 112 (13.8 g) as white needles.

[0573]¹H NMR (DMSO-d₆) δ 6.96 (d, J=8.3 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H),6.50 (dd, J=8.3, 2.3 Hz, 1H).

Example 113

[0574] 2-Amino-4-methyl-benzenethiol hydrochloride (113)

[0575] bis-(4-Methyl-2-nitrophenyl)-trisulfide was prepared using themethod in Example 112, starting from 4-chloro-3-nitro-toluene (Aldrich,34.3 g, 200 mmol), sulfur (Aldrich, 9.6 g, 300 mmol) and sodium sulfidenonahydrate (Aldrich, 24.0 g, 100 mmol) in 95% EtOH (150 mL). 27.7 g ofthe trisulfide was obtained as a yellow solid.

[0576]¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J=8.3 Hz, 1H), 8.07 (br s, 1H),7.58 (dd, J=8.3, 1.3 Hz, 1H), 2.48 (s, 3H).

[0577] Reduction of the bis-(4-Methyl-2-nitrophenyl)trisulfide as inExample 112 gave compound 113 (11.3 g) as a mixture afterrecrystalization, but which was used directly in subsequent reactions.

Example 114

[0578] 5-Chloro-2-(2,6-dichloro-4-nitro-benzyl)-benzothiazole (114)

[0579] By a modification of the procedure of D. L. Boger (J. Org. Chem.43, 2296-2297 (1978) a solution of P₂O₅/MeSO₃H (Aldrich, 7.5 g, 1:10,w:w) was treated with 2-amino-4-chloro-benzenethiol hydrochloride(Example 112, 1.96 g, 10.0 mmol) and(2,6-dichloro-4-nitro-phenyl)-acetic acid (Example 110, 2.50 g, 10.0mmol). The resulting mixture was stirred at room temperature for 1 hour,then heated at 90° C. overnight (15 hours). After cooled to roomtemperature, the reaction mixture was poured to ice and the resultingmixture was extracted 3× with EtOAc (50 mL). The organic layers werecombined and washed twice with a brine solution (100 mL), dried overNa₂SO₄, and concentrated under vacuum. The crude solid waschromatographed (CH₂Cl₂) to yield 3.7 g (99%) of compound 114 as a paleyellow solid.

[0580]¹H NMR (CDCl₃) δ 8.28 (s, 2H), 7.98 (d, J=1.9 Hz, 1H), 7.76 (d,J=8.5 Hz, 1H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 4.87 (s, 2H). MS (M+H) 373.

[0581] The compounds of Table 18 were prepared using the method ofexample 114. TABLE 18

Example A B yield 114 Cl Cl 99% 115 Cl H 98% 116 CF₃ Cl 96% 117 CF₃ H89% 118 H Cl 92% 119 H H 77% 120 Me Cl 20% 121 Me H 28%

Example 115

[0582] 5-Chloro-2-(2-chloro-4-nitro-benzyl)-benzothiazole

[0583]¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=2.3 Hz, 1H), 8.25 (dd,J=8.5, 2.4 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.89(d, J=8.5 Hz, 1H), 7.48 (dd, J=8.6, 2.0 Hz, 1H), 4.77 (s, 2H). MS (M+H)339.

Example 116

[0584] 2-(2,6-Dichloro-4-nitro-benzyl)-5-trifluoromethyl-benzothiazole

[0585]¹H NMR (DMSO-d₆) δ 8.42 (s, 2H), 8.34 (d, J=8.4 Hz, 1H), 8.28 (brs, 1H), 7.76 (d, J=8.4 Hz, 1H), 4.94 (s, 2H). MS (M+H) 407.

Example 117

[0586] 2-(2-Chloro-4-nitro-benzyl)-5-trifluoromethyl-benzothiazole

[0587]¹H NMR (CDCl₃) δ 8.33 (d, J=2.3 Hz, 1H), 8.27 (br s, 1H), 8.14(dd, J=8.5, 2.3 Hz, 1H), 7.96 (br d, J=8.3 Hz, 1H), 7.63 (d, J=8.5 Hz,2H) 4.70 (s, 2H), Ms (M+H) 371.

Example 118

[0588] 2-(2,6Dichloro-4-nitro-benzyl)-benzothiazole

[0589]¹H NMR (DMSO-d₆) δ 8.41 (s, 2H), 8.06 (d, J=8.0 Hz, 1H), 7.90 (d,J=7.9 Hz, 1H), 7.50-7.38 (m, 2H), 4.94 (s, 2H). MS (M−H) 337.

Example 119

[0590] 2-(2-Chloro-4-nitro-benzyl)-benzothiazole

[0591]¹H NMR (CDCl₃) δ 8.35 (d, J=2.2 Hz, 1H), 8.25 (dd, J=8.4, 2.2 Hz,1H), 8.05 (d, J=7.9 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.86 (d, J=8.5 Hz,1H), 7.49 (t, J=7.9 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 4.76 (s, 2H). MS(M+H) 305.

Example 120

[0592] 2-(2,6-Dichloro-4-nitro-benzyl)-5-methyl-benzothiazole

[0593]¹H NMR (DMSO-d₆) δ 8.41 (s, 2H), 7.91 (d, J=8.2 Hz, 1H), 7.71 (brs, 1H), 7.25 (d, J=8.2 Hz, 1H), 4.85 (s, 2H), 2.41 (s, 3H). MS (M+H)353.

Example 121

[0594] 2-(2-Chloro-4-nitro-benzyl)-5-methyl-benzothiazole

[0595]¹H NMR (DMSO-d₆) δ 8.35 (d, J=2.3 Hz, 1H), 8.24 (dd, J=8.5, 2.3Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.74 (br s,1H), 7.25 (dd, J=8.2, 1.0 Hz, 1H), 4.73 (s, 2H), 2.42 (s, 3H). MS (M−H)317.

[0596] Reduction of the compounds of Table 18 gave the anilines of Table19. TABLE 19

Example A B Method yield 122 Cl Cl A 100%  123 Cl H B 88% 124 CF₃ Cl A90% 125 CF₃ H B 89% 126 H Cl B 97% 127 H H B 90% 128 Me Cl B 97% 129 MeH B 97% Method A: see example 90 Method B: see example 181

Example 122

[0597] 3,5-Dichloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenylamine

[0598]¹H NMR (DMSO-d₆) δ 8.03 (d, J=8.4 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H),7.45 (dd, J=8.5, 2.2 Hz, 1H), 6.70 (s, 2H), 5.79 (s, 2H), 4.52 (s, 2H).MS (M+H) 343.

Example 123

[0599] 3-Chloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenylamine

[0600]¹H NMR (DMSO-d₆) δ 8.05-7.95 (m, 2H), 7.43 (dd, J=8.5, 2.1 Hz,1H), 7.17 (d, J=8.2 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.53 (dd, J=8.2,2.2 Hz, 1H), 5.44 (s, 2H), 4.36 (s, 2H). MS (M+H) 309.

Example 124

[0601]3,5-Dichloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenylamine

[0602]¹H NMR (DMSO-d₆) δ 8.29 (br s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.72(d, J=8.4 Hz, 1H), 6.70 (s, 2H), 5.81(s, 2H), 4.56 (s, 2H). MS (M+H)377.

Example 125

[0603]3-Chloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenylamine

[0604]¹H NMR (DMSO-d₆) δ 8.25 (br s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.72(dd, J=8.4, 1.3 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 6.67 (d, J=2.2 Hz, 1H),6.54 (dd, J=8.2, 2.2 Hz, 1H), 5.46 (s, 2H), 4.40 (s, 2H). MS (M+H) 343.

Example 126

[0605] 4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenylamine

[0606]¹H NMR (DMSO-d₆) δ 7.99 (dd, J=8.0, 0.6 Hz, 1H), 7.92 (d, J=8.1Hz, 1H), 7.45 (td, J=8.2, 1.2 Hz, 1H), 7.38 (td, J=8.0, 1.0 Hz, 1H),6.70 (s, 2H), 5.78(s, 2H), 4.51 (s, 2H). MS (M+H) 309.

Example 127

[0607] 4-Benzothiazol-2-ylmethyl-3-chloro-phenylamine

[0608]¹H NMR (DMSO-d₆) δ 7.98 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H),7.47 (td, J=7.9, 1.2 Hz, 1H), 7.38 (td, J=7.9, 1.0 Hz, 1H), 7.17 (d,J=8.3 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.54 (dd, J=8.2, 2.2 Hz, 1H),5.44 (s, 2H), 4.35 (s, 2H). MS (M+H) 275.

Example 128

[0609] 3,5-Dichloro-4-(5-methyl-benzothiazol-2-ylmethyl)-phenylamine

[0610]¹H NMR (DMSO-d₆) δ 7.84 (d, J=8.2 Hz, 1H), 7.73 (br s, 1H), 7.21(dd, J=8.2, 1.0 Hz, 1H), 6.69 (s, 2H), 5.77 (s, 2H), 4.48 (s, 2H), 2.43(s, 3H). MS (M+H) 323.

Example 129

[0611] 3-Chloro-4-(5-methyl-benzothiazol-2-ylmethyl)-phenylamine

[0612]¹H NMR (DMSO-d₆) δ 7.84 (d, J=8.2 Hz, 1H), 7.73 (s, 1H), 7.21 (d,J=8.2 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 6.65 (d, J=2.1 Hz, 1H), 6.52 (dd,J=8.2, 2.1 Hz, 1H), 5.41 (s, 2H), 4.32 (s, 2H), 2.43 (s, 3H). MS (M+H)289.

[0613] The compounds of Table 20 were prepared using the method ofexample 94 from compounds in Table 19 and corresponding arylsulfonylchloride. TABLE 20

Example A B D E yield 130 Cl Cl CF₃ H 83% 131 Cl Cl Cl H 63% 132 Cl ClCl Me 73% 133 Cl H CF₃ H 78% 134 CF₃ Cl CF₃ H 74% 135 CF₃ Cl Cl H 82%136 CF₃ H CF₃ H 55% 137 CF₃ H Cl H 26% 138 H Cl CF₃ H 67% 139 H Cl Cl H55% 140 H Cl Cl Me 85% 141 H H CF₃ H 64% 142 Me Cl CF₃ H 84% 143 Me HCF₃ H 88%

Example 130

[0614]2-Chloro-N-[3,5-dichloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide

[0615]¹H NMR (DMSO-d₆) δ 11.56 (br s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.20(d, J=1.1 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.00-7.95 (m, 2H), 7.45 (dd,J=8.6, 2.1 Hz, 1H), 7.23 (s, 2H), 4.62 (s, 2H). MS (M−H) 583.

Example 131

[0616]2,4-Dichloro-N-[3,5-dichloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide

[0617]¹H NMR (DMSO-d₆) δ 11.40 (br s, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.05(d, J=8.6 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 7.70(dd, J=8.6, 2.1 Hz, 1H), 7.46 (dd, J=8.6, 2.0 Hz, 1H), 7.20 (s, 2H),4.62 (s, 2H). MS (M−H) 549.

Example 132

[0618]2,4-Dichloro-N-[3,5-dichloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]-5-methyl-benzenesulfonamide

[0619]¹H NMR (DMSO-d₆) δ 11.33 (br s, 1H), 8.28 (s, 1H), 8.17 (s, 1H),8.04 (d, J=8.6 Hz, 1H), 8.01 (d, J=1.9 Hz, 1H), 7.87 (s, 1H), 7.45 (dd,J=8.6, 1.9 Hz, 1H), 7.22 (s, 2H), 4.61 (s, 2H), 2.40 (s, 3H). MS (M−H)563.

Example 133

[0620]2-Chloro-N-[3-chloro-4-(5-chloro-benzothiazol-2-ylmethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide

[0621]¹H NMR (DMSO-d₆) δ 11.24 (br s, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.16(br s, 1H), 8.02 (d, J=8.6 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.96 (d,J=8.3 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.20 (d, J=2.0 Hz, 1H), 7.10 (dd,J=8.4, 2.0 Hz, 1H), 4.47 (s, 2H), MS (M−H)z 549.

Example 134

[0622]2-Chloro-N-[3,5-dichloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide

[0623]¹H NMR (DMSO-d₆) δ 11.56 (s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.27 (d,J=8.3 Hz, 1H), 8.26 (br s, 1H), 8.20 (br s, 1H), 7.99 (dd, J=8.3, 1.0Hz, 1H), 7.73 (dd, J=8.2, 1.2 Hz, 1H), 7.24 (s, 2H), 4.67 (s, 2H). MS(M−H) 617.

Example 135

[0624]2,4-Dichloro-N-[3,5-dichloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide

[0625]¹H NMR (DMSO-d₆) δ 11.41 (s, 1H), 8.29 (br s, 1H), 8.27 (d, J=8.6Hz, 11H), 8.15 (d, J=8.6 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.73 (dd,J=8.4, 1.4 Hz, 1H), 7.70 (dd, J=8.6, 2.0 Hz, 1H), 7.21 (s, 2H), 4.67 (s,2H). MS (M−H).

Example 136

[0626]2-Chloro-N-[3-chloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide

[0627]¹H NMR (DMSO-d₆) δ 11.25 (br s, 1H), 8.32-8.22 (m, 3H), 8.16 (brs, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.46 (d, J=8.3Hz, 1H), 7.21 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.52 (s, 2H). MS (M−H)583.

Example 137

[0628]2,4-Dichloro-N-[3-chloro-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-phenyl]-benzenesulfonamide

[0629]¹H NMR (DMSO-d₆) δ 11.10 (br s, 1H), 8.28 (br s, 1H), 8.26 (d,J=8.5 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.72 (dd,J=8.4, 1.4 Hz, 1H), 7.65 (dd, J=8.6, 2.1 Hz, 1H), 7.46 (d, J=8.4 Hz,11H), 7.18 (d, J=2.2 Hz, 1H), 7.10 (dd, J=8.3, 2.2 Hz, 1H), 4.52 (s,2H). MS (M−H) 549.

Example 138

[0630]N-(4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenyl)-2-chloro-4-trifluoromethyl-benzenesulfonamide

[0631]¹H NMR (DMSO-d₆) δ 11.54 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.20 (brs, 1H), 7.99 (d, J=8.3 Hz, 2H), 7.88 (d, J=7.8 Hz, 1H), 7.46 (td, J=8.0,1.0 Hz, 1H), 7.40 (td, J=7.8, 0.9 Hz, 1H), 7.23 (s, 2H), 4.61 (s, 2H).MS (M−H) 549.

Example 139

[0632]N-(4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenyl)-2,4-dichloro-benzenesulfonamide

[0633]¹H NMR (DMSO-d₆) δ 11.38 (s, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.00 (d,J=7.9 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.70 (dd,J=8.6, 2.0 Hz, 1H), 7.46 (m, 1H), 7.40 (m, 1H), 7.20 (s, 2H), 4.60 (s,2H). MS (M−H) 515.

Example 140

[0634]N-(4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenyl)-2,4-dichloro-5-methyl-benzenesulfonamide

[0635]¹H NMR (DMSO-d₆) δ 11.32 (s, 1H), 8.17 (s, 1H), 8.00 (d, J=7.9 Hz,1H), 7.90 (d, J=8.1 Hz, 1H), 7.88 (s, 1H), 7.46 (t, J=7.3 Hz, 1H), 7.39(t, J=7.4 Hz, 1H), 7.16 (s, 2H), 4.60 (s, 2H), 2.40 (s, 3H). MS (M−H)531.

Example 141

[0636]N-(4-Benzothiazol-2-ylmethyl-3-chloro-phenyl)-2-chloro-4-trifluoromethyl-benzenesulfonamide

[0637]¹H NMR (DMSO-d₆) δ 11.23 (br s, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.15(br s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.90 (d,J=8.1 Hz, 1H), 7.46 (td, J=7.9, 1.0 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H),7.38 (t, J=7.7 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.11 (dd, J=8.3, 2.1 Hz,1H), 4.46 (s, 2H). MS (M−H) 517.

Example 142

[0638]2-Chloro-N-[3,5-dichloro-4-(5-methyl-benzothiazol-2-ylmethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide

[0639]¹H NMR (DMSO-d₆) δ 11.54 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.19 (brs, 1H), 8.00 (dd, J=8.2, 1.0 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.70 (brs, 1H), 7.26-7.18 (m, 3H), 4.58 (s, 2H), 2.40 (s, 3H). MS (M−H) 563.

Example 143

[0640]2-Chloro-N-[3-chloro-4-(5-methyl-benzothiazol-2-ylmethyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide

[0641]¹H NMR (DMSO-d₆) δ 11.22 (br s, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.15(br s, 1H), 7.45 (dd, J=8.3, 1.1 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.71(br s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.24-7.19 (m, 2H), 7.05 (dd, J=8.5,2.2 Hz, 1H), 4.43 (s, 2H), 2.41 (s, 3H). MS (M−H) 529.

Example 144

[0642] This Example illustrates the synthesis of 144.1.

[0643] Nitro compound 109.1 (1.91 g, 5.8 mmol) was reduced to thecorresponding aniline using SnCl₂.2H₂O (6.54 g, 29.0 mmol) in EtOAc (40mL) according to the procedure previously described in Example 30. Thisyielded 692 mg (40%) of compound 144.1 as a white powder.

[0644] MS ESI m/e: 300.0 (M+H).

Example 145

[0645] This Example illustrates the synthesis of 145.1.

[0646] A round-bottomed flask was charged with aniline 144.1 (110 mg,0.37 mmol), 2,4-dichlorobenzenesulfonyl chloride (108 mg, 0.44 mmol),2,6-lutidine (47 mg, 0.44 mmol), catalytic DMAP, and methylene chloride(2.0 mL). The reaction was allowed to stir overnight. The reaction wasthen diluted with 20 mL of methylene chloride and washed with 10 mL of1N HCl and 10 mL of brine. The organics were dried over Na₂SO₄ andconcentrated to a yellow oil. This oil was further purified using silicagel flash chromatography. The desired fractions were combined andconcentrated to yield 60 mg (32%) of compound 145.1 as a white foam.

[0647]¹H NMR (400 MHz) (d₆-DMSO) δ 11.36 (1H, s); 8.12 (1H, d, J=8.6Hz); 7.94 (1H, d, J=2.1 Hz); 7.68 (1H, dd, J=8.6, 2.1 Hz); 8.63 (1H, d,J=8.4 Hz); 7.47 (1H, d, J=8.4 Hz); 7.36-7.32 (1H, m); 7.27-7.19 (4H, m);2.54 (2H, q, J=7.6 Hz); 1.08 (3H, t, J=7.6 Hz). MS ESI m/e: 506.0 (M−H).

Example 146

[0648] This Example illustrates the synthesis of 146.1.

[0649] Aniline 144.1 (111 mg, 0.37 mmol), pipsyl chloride (135 mg, 0.45mmol), 2,6-lutidine (48 mg, 0.45 mmol), and catalytic DMAP were combinedin methylene chloride (2.0 mL) according to the procedure described inExample 77. This yielded 140 mg (67%) of compound 146.1 as a white foam.

[0650]¹H NMR (400 MHz) (d₆-DMSO) δ 10.97 (1H, s); 8.01 (2H, d, J=8.4Hz); 7.63 (1H, d, J=8.4 Hz); 7.58 (2H, d, J=8.4 Hz); 7.46 (1H, d, J=8.4Hz); 7.34 (1H, m); 7.46-7.20 (4H, m); 2.54 (2H, q, J=7.5 Hz); 1.09 (3H,t, J=7.5 Hz). MS ESI m/e: 563.9 (M−H).

Example 147

[0651] This Example illustrates the synthesis of 147.1.

[0652] Aniline 144.1 (108 mg, 0.36 mmol), 3,4-dichlorobenzenesulfonylchloride (106 mg, 0.43 mmol), 2,6-lutidine (46 mg, 0.43 mmol), andcatalytic DMAP were combined in methylene chloride (2.0 mL) according tothe procedure described in Example 77. This yielded 113 mg (62%) ofcompound 147.1 as a white foam.

[0653]¹H NMR (400 MHz) (CDCl₃) δ 7.96 (1H, d, J=2.2 Hz); 7.66 (1H, dd,J=8.4, 2.2 Hz); 7.57 (1H, d, J=8.4 Hz); 7.46 (1H, d, J=8.3 Hz); 7.34(1H, d, J=8.3 Hz); 7.31-7.26 (3H, m); 7.20-7.15 (2H, m); 2.79 (2H, q,J=7.6 Hz); 1.27 (3H, t, J=7.6 Hz). MS ESI m/e: 506.0 (M−H).

Example 148

[0654] This illustrates the synthesis of (2-fluoro-4-nitro-phenyl)aceticacid 148.

[0655] A round-bottomed flask was charged with diethyl malonate (8.6 g,54 mmol), cesium carbonate (29.3 g, 90 mmol), and anhydrous DMF (36 mL).The mixture was warmed to 70° C. and 2,4-difluoronitrobenzene (5.75 g,36 mmol) was added in a dropwise fashion with vigorous stirring. Thereaction medium immediately turned dark purple. After the addition wascomplete, the reaction was stirred at 70° C. for 30 minutes. Aftercooling to room temperature, the reaction was quenched with 4 mL ofacetic acid and then poured into 300 mL of 0.3 N HCl_((aq)). The purplecolor discharged completely upon addition to the acid. The mixture wasthen neutralized by adding solid NaHCO₃ until no gas evolution tookplace. The mixture was extracted 2×150 mL 1:1 diethyl ether:hexanes. Thecombined organic layers were washed 2×100 mL DI water and 1×50 mL sat.brine. The organic layer was dried over MgSO₄ and concentrated to ayellow oil. This oil was suspended in 40 mL of 6N HCl_((aq)) and themixture heated to reflux for 16 h. Upon cooling, crystals separated andwere collected by filtration. The crystals were dried under vacuum toyield 2-fluoro-4-nitro-phenylacetic acid (148) as off-white crystals(5.42 g).

[0656]¹H NMR (400 MHz) (d₄-MeOH) δ 8.06 (1H, d); 8.04 (1H, d); 7.60 (1H,t); 3.81 (2H, s).

Example 149

[0657] This illustrates the synthesis of7-chloro-2-(2-fluoro-4-nitro-benzyl)-benzoxazole 149.

[0658] The benzoxazole 149 was formed according to the method ofTerashima and Ishi (Synthesis 1982, 484-85.). Phenylacetic acid 148 (387mg, 1.95 mmol), 2-amino-6-chloro-phenol (233 mg, 1.67 mmol, described inJ. Med. Chem. 1996, 39, 3435-3450), and boric acid (120 mg, 1.95 mmol)were combined in xylenes (24 mL) and the mixture heated to reflux in aflask equipped with a Dean-Stark trap. After 8 h, the reaction mixturewas filtered, concentrated, and the residue purified by flashchromatography (silica gel, 3:1 hexanes:ethyl acetate). Fractionscontaining benzoxazole 149 were concentrated to a yellow solid (419 mg).

[0659]¹H NMR (CDCl₃) δ 8.05 (d, 1H); 8.00 (dd, 1H); 7.61 (d, 1H); 7.57(d, 1H); 7.33 (d, 1H); 7.27 (d, 1H) 4.38 (s, 2H). MS (M+H) 307.0.

Example 150

[0660] This illustrates the synthesis of compound 150.

[0661] A round-bottomed flask was charged with2-mercapto-5-methylbenzimidazole (4.84 g, 29.5 mmol), potassiumhydroxide (1.66 g, 29.5 mmol), and water (18 mL). This suspension washeated to 120° C. for 3.0 hours. Then 3,4,5-trichloronitrobenzene (6.68g, 29.5 mmol) dissolved in 53 mL of n-butanol was added dropwise whilethe reaction stirred at 120° C. All the white solids went into solutionand the solution proceeded to turn a deep red color. The reaction wasleft stirring for five days, at which point a yellow precipitate wasseen. The reaction was then cooled to room temperature and theprecipitate was filtered and washed with distilled water to yield 8.10 g(78%) of compound 150 as canary yellow crystals which were a 50/50mixture of both possible tautomers.

[0662]¹H NMR (400 MHz) (d₆-DMSO) δ 12.64 (1H, s); 8.48 (2H, d, J=2.2Hz); 7.34 and 7.27 (1H, 2 tautomeric doublets, J=8.3 Hz); 7.26 and 7.19(1H, 2 tautomeric singlets); 6.99 and 6.95 (1H, 2 tautomeric doublets,J=8.1 Hz); 2.38 and 2.35 (3H, 2 tautomeric singlets).

Example 151

[0663] This illustrates the synthesis of compound 151.

[0664] A round-bottomed flask was charged with 8.1 g (22.8 mmol) ofcompound 150, 20.6 g (91.4 mmol) of tin dichloride dihydrate, and 150 mLof EtOAc. This was heated to 75° C. for 3.0 hours. The reaction wascooled to room temperature, diluted with 300 mL of EtOAc and washed with250 mL of 2N aqueous KOH solution followed by 200 mL of brine. Theorganics were dried over sodium sulfate and concentrated to 7.4 g (94%)of 151 as a pale yellow solid that was used without furtherpurification. MS (M+H) 324

Example 152

[0665] This illustrates the synthesis of compound 152.

[0666] A round-bottomed flask was charged with compound 151 (749 mg,2.31 mmol), 4-acetylbenzenesulfonyl chloride (1.01 g, 4.62 mmol),2,6-lutidine (496 mg, 4.62 mmol), acetone (4.0 mL), and a catalyticamount of DMAP. This was stirred at room temperature for 12 hours, afterwhich 2,6-lutidine hydrochloride was seen as a white precipitate. Thereaction was diluted with 40 mL of EtOAc and washed with 30 mL of 1Naqueous HCl followed by 30 mL of brine. The organics were dried overmagnesium sulfate and concentrated to a clear oil that was dissolved in30 mL of THF. To this was added 30 mL of 0.5N aqueous KOH. This wasstirred at room temperature for 12 hours, and the reaction colorprogressed from a light yellow to a deep orange. Next, the pH wasbrought to 7.0 with 1.0N HCl and the THF was removed in vacuo. Theremaining aqueous phase was extracted with 100 mL of Et₂O. The organiclayer was dried over sodium sulfate and concentrated to a yellow oilthat was further purified with silica gel flash chromatography (3:2hexanes:EtOAc). The desired fractions were combined and concentrated toan oil which was recrystallized from hot EtOAc/hexanes to yield 312 mg(27%) of 152 as an off-white solid. MS (M−H) 504.

[0667]¹H NMR (d₆-DMSO) δ 12.36 (1H, broad s); 11.39 (1H, broad s); 8.18(2H, t); 8.03 (2H, t); 7.32 (2H, s); 7.32-7.04 (2H, m); 6.96 (1H, m);2.62 (3H, s) 2.35 (3H, s).

Example 153

[0668] This illustrates the synthesis of compound 153.

[0669] Compound 153 was prepared according to Example 152. In this case,353 mg (1.1 mmol) of compound 151 was used to give 76 mg (14%) of 153 aswhite crystals.

[0670]¹H NMR (d₆-DMSO) δ 12.31 (1H, broad s); 11.42 (1H, broad s); 8.90(1H, d); 8.29 (1H, dd); 7.81 (1H, d); 7.34 (2H, s); 7.26 (1H, broad s);7.17 (1H, broad s); 6.92 (1H, d); 2.35 (3H, s). MS (M−H) 497.0.

[0671] The additional examples of Table 21 were prepared according tothe method of Example 152. TABLE 21

V A B C D m/e (M − H) 152 Cl H H —C(═O)Me H 504 153 Cl[2-chloro-5-pyridyl] 497 154 Cl Me H Cl Me 524 155 Cl Cl H Cl H 530 156Cl Cl H CF₃ H 564 157 Cl Cl H Cl Me 544 158 H Cl H Cl H 496 159 H H ClCl H 496 160 H Cl H CF₃ H 530 161 H Cl H Cl Me 510 162 H H H I H 554 163H [2-chloro-5-pyridyl] 463 164 H Me H Cl Me 490

Example 154

[0672]¹H NMR (d₆-DMSO) δ 12.29 (1H, broad s); 11.37 (1H, broad s); 8.01(1H, s); 7.57 (1H, s); 7.19-7.33 (4H, m); 6.91 (1H, s); 2.57 (3H, s);2.38 (3H, s); 1.24 (3H, s). MS (M−H) 524.

Example 155

[0673] MS (M−H) 529.8. ¹H NMR (d₆-DMSO) δ 12.31 (1H, broad s); 11.64(1H, broad s); 8.18 (1H, d); 7.94 (1H, d); 7.71 (1H, dd); 7.34-7.09 (4H,m); 6.93 (1H, d); 2.33 (3H, s).

Example 156

[0674] MS (M−H) 564. ¹H NMR (d₆-DMSO) δ 12.28 (1H, broad s); 11.80 (1H,broad s); 8.38 (1H, d); 8.19 (1H, s); 8.00 (1H, d); 7.29 (2H, s); 7.24(1H, broad s); 7.15 (1H, broad s); 6.91 (1H, d); 2.34 (3H, s).

Example 157

[0675] MS (M−H) 544. ¹H NMR (d₆-DMSO) δ 12.29 (1H, broad s); 11.58 (1H,s); 8.22 (1H, s); 7.89 (1H, s); 7.29 (2H, s); 7.24 (1H, broad s); 7.16(1H, broad s); 6.91 (1H, d); 2.41 (3H, s); 2.34 (3H, s).

[0676] The examples of Table 22 were prepared by analogy to the methodsof Examples 150-152. TABLE 22

A B C D m/e (M − H) 165 Cl H Cl Me 496 166 Cl H Cl H 482 167 H H I H 540168 H Cl Cl H 482 169 Cl H CF₃ H 516 170 Me H Cl Me 476

[0677] The examples of Table 23 were prepared by analogy to the methodsof Examples 150-152. TABLE 23

A B C D m/e (M − H) 171 Cl H Cl H 584 172 Cl H CF₃ H 618 173 Me H Cl Me578

Example 174

[0678]

[0679] 3-Hydroxyquinoline (prepared according to the procedure ofNaumann, et. al., Synthesis, 1990, 4, 279-281)) (3 g) and1,2,3-trichloro-5-nitrobenzene (4.7 g) were dissolved in DMF (80 mL) andheated with cesium carbonate (7.4 g) for 2 hr at 60° C. The reaction waspoured into ice/water (500 ml). The resulting off-white precipitate wascollected by filtration and rinsed with hexane to afford compound 174 asa solid (6.9 g) suitable for use in the next reaction.

[0680]¹H NMR in CDCl₃ 8.863 (d, J=2.2 Hz, 1H), 8.360 (s, 2H), 8.106 (d,J=8.6 Hz, 1H), 7.646 (m, 2H), 7.529 (d, J=8.6 Hz, 1H), 7.160 (d, J=2.2Hz, 1H).

Example 175

[0681] To a solution of compound 180 (6.9 g) in ethanol/THF/water (ratio40:20:10) was added ammonium chloride (3.3 g) and powdered iron (3.4 g).This mixture was heated to reflux for 5 hr. The hot mixture was thenfiltered through Celite and concentrated. The residue was dissolved inethyl acetate and washed with saturated NaHCO₃ solution followed bywater and then brine. The solution was dried over magnesium sulfate andconcentrated to afford compound 175 as an off-white solid (5.6 g).

[0682]¹H NMR in (DMSO) δ 8.846 (d, J=2.9 Hz, 1H), 8.010 (m, 1H), 7.915(m, 1H), 7.645 (m, 1H), 7.560 (m, 1H), 7.401 (d, J=2.9 Hz, 1H), 6.778(s, 2H), 5.762 (s, 2H).

[0683] Treatment of the aniline 175 with various sulfonyl chloridesaccording to conventional methods gave the sulfonamides of Table 24.TABLE 24

Example X V V A B C D 176 H H Cl CF₃ H Cl H 177 H H Cl Cl H CF₃ H 178 HH Cl Cl H Cl H 179 H H Cl Cl H Cl Me 180 H H H Cl H Cl H 181 —CO₂Me H ClCl H Cl H 182 H —CO₂Me Cl Cl H Cl H 183 —CO₂H H Cl Cl H Cl H 184 H —CO₂HCl Cl H Cl H 185 Me H Cl Cl H Cl Me 186 H H F Cl H Cl Me

Example 176

[0684]¹H NMR (DMSO) δ 11.4-11.6 (1H, broad), 8.87 (1H, d, J=2.9 Hz),8.15-8.22 (2H, m), 8.00-8.08 (2H, m), 7.87 (1H, d, J=8.0 Hz), 7.55-7.68(2H, m), 7.47 (1H, d, J=2.9 Hz), 7.35 (2H, s). MS (M−H) 545. mp 98.8° C.

Example 177

[0685]¹H NMR(DMSO) δ 11.58 (1H, s), 8.86 (1H, d, J=2.9 Hz), 8.38 (1H, d,J=8.4 Hz), 8.23 (1H, s), 8.01 (1H, d, J=8.4 Hz), 7.86 (1H, d, J=8.1 Hz),7.53-7.68 (2H, m), 7.46 (1H, d, J=2.9 Hz), 7.34 (2H, s). MS (M−H) 545.0.

Example 178

[0686]¹H NMR(d₆-acetone) 9.9 (1H, br s), 8.794 (1H, d, J=2.9 Hz), 8.23(1H, d, J=8.4 Hz), 8.035 (1H, br d, J=8.4 Hz), 7.793 (1H, d, J=1.5 Hz),7.78 (1H, m), 7.62-7.70 (2H, m), 7.57 (1H, td, J=6.8,1.2 Hz), 7.476 (2H,s), 7.364 (1H, d, J=2.6 Hz). MS (M−H) 511.0.

Example 179

[0687]¹H NMR(300 MHz/CDCl₃) δ 2.43 (3H, s ), 7.10 (1H, d, J=3 Hz), 7.26(2H, s), 7.48-7.64 (4H, m), 7.96 (1H, s ), 8.09 (1H, d, J=8.7 Hz), 8.78(1H, d, J=3 Hz). MS (M+H) 527. mp 233-235°.

Example 180

[0688]¹H NMR(300 MHz/CDCl₃) δ 7.14 (1H, dd, J=2.6 Hz, J=8.9 Hz), 7.26(1H, d, J=8.9 Hz), 7.33 (1H, d, J=2.6 Hz), 7.56-7.58 (2H, m), 7.66-7.69(2H, m), 7.87(1H, m), 7.93 (1H, d, J=2.0 Hz), 8.00(1H, m ), 8.09 (1H, d,J=8.5 Hz), 8.80 (1H, d, J=2.9 Hz), 11.06 (1H, br s). MS (M+H)) 479 mp122° C.

Example 181

[0689]3-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-6-carboxylicacid methyl ester (181)

[0690] A solution of3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-6-carboxylic acid methylester (312) (0.93 mmol) and 2,4-dichlorobenzenesulfonyl chloride (250mg, 1.02 mmol) in Pyridine (0.13 ml, 1.53 mmol)-CH₂Cl₂ (3.7 ml) wasstirred at room temperature for 12 hr. Sat NaHCO₃ was added to thereaction mixture, which was then extracted twice with AcOEt. Organiclayer was washed by brine, dried over anhydrous MgSO₄, and concentrated.Crude residue was purified by column chromatography (Hexane/AcOEt=2/1,80 g of silica gel) to afford compound 181 (237 mg, 41%, in 3 steps).

[0691]¹H NMR (300 MHz, DMSO-d₆) δ 3.90 (3H, s), 7.31(2H, s), 7.72 (1H,dd, J=1.8, 7.8 Hz), 7.79 (1H, d, J=3.0 Hz), 7.96 (1H, d, J=1.8 Hz), 8.11(2H, s), 8.18 (1H, d, J=7.8 Hz), 8.64 (1H, s), 8.99 (1H, d, J=3.0 Hz),11.42 (1H, br s). MS (M+H) 571.

Example 182

[0692]3-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-8-carboxylicacid methyl ester (182)

[0693] To a solution of3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-8-carboxylic acid methylester (315) (1.26 mmol) in Pyridine (0.15 ml, 1.80mmol) and CH₂Cl₂ (5ml), was added 2,4-Dichlorolbenzenesulfonyl chloride (381 mg, 1.55mmol). The mixture was stirred at room temperature for 12 hr. Sat NaHCO₃was added to the reaction mixture, which was then extracted twice withAcOEt. Organic layer was washed by Brine, dried over MgSO₄, andconcentrated. The crude residue was purified by column chromatography(Hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 182 (506 mg,70%) as a white solid.

[0694]¹H NMR (300 MHz, DMSO-d₆) δ 3.91 (3H, s), 7.31(2H, s), 7.57-7.65(2H, m), 7.72 (1H, dd, J=2.1, 8.6 Hz), 7.83 (1H, d, J=8.6 Hz), 7.96 (2H,d, J=2.1 Hz), 8.03 (1H, d, J=8.6 Hz), 8.18 (1H, d, J=8.6 Hz), 8.94 (1H,d, J=2.1 Hz), 11.4 (1H, br s), MS (M+H) 571.

Example 183

[0695]3-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-6-carboxylicacid (183)

[0696] To a solution of3-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-6-carboxylicacid methyl ester (181) (200 mg, 0.35 mmol) in THF/MeOH(2 ml/2 ml) wasadded 4N NaOH (0.1 ml, 0.4 mmol). This mixture was refluxed for 2.5 hr.The reaction mixture was cooled to room temperature and was neutralizedwith 2N HCl, and then concentrated. The residue was extracted twice withAcOEt. Organic layer was washed by Brine, dried over anhydrous MgSO₄,and concentrated to give a solid. Crude product was recrystallized byHexane/AcOEt to afford compound 183(153 mg, 78%).

[0697]¹H NMR (300 MHz, DMSO-d₆) δ 7.16 (2H, s), 7.62 (1 H, dd, J=2.0,8.5 Hz), 7.73 (1H, d, J=2.9 Hz), 7.82 (1H, s), 8.08-8.11 (3H, m), 8.60(1H, s), 8.95 (1H, d, J=2.9 Hz), 13.2 (1H, br s), MS (M+H) 557. mp228-2.

Example 184

[0698]3-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-8-carboxylicacid (184)

[0699] To a solution of3-[2,6-Dichloro-4-(2-chloro-4-trifluoromethyl-benzenesulfonylamino)-phenoxy]-quinoline-8-carboxylicacid methyl ester (183) (402 mg, 0.7 mmol) in THF/MeOH=0.1 ml/0.3 ml wasadded 4N NaOH (0.2 ml, 0.77 mmol). The mixture was refluxed for 12 hr.After cooling to room temp. the reaction mixture was filtered to removeinsoluble materials. The filtrate was concentrated and the residue wasdissolved in aq NH₄Cl and extracted twice with AcOEt. Organic layer waswashed by Brine, and dried over anhydrous MgSO₄, and concentrated toafford compound 184 (197 mg, 50%) as a white solid.

[0700]¹H NMR (300 MHz, DMSO-d₆) δ 7.32 (2H, s), 7.70-7.81 (2H, m), 7.90(1H, d, J=2.2 Hz), 7.96 (1H, d, J=2.2 Hz), 8.17-8.19 (1H, m), 8.22-8.24(1H, m), 8.3-8.39 (1H, m), 9.11 (1H, d, J=2.2 Hz), 11.4 (1H, br s), 15.4(1H, br s), MS (M+H) 557. mp 263-266° C.

Example 185

[0701]2,4-Dichloro-N-[3,5-dichloro-4-(6-methyl-quinoln-3-yloxy)-phenyl]-5-methyl-benzenesulfonamide(185)

[0702] To a solution of3,5-Dichloro-4-(6-methyl-quinlin-3-yloxy)-phenylamine (339) (400 mg,1.25 mmol) in Pyridine (0.12 ml, 1.48 mmol)-CH₂Cl₂ (4 ml) was added2,4-Dichloro-5-methylbenzenesulfonyl chloride (325 mg, 1.25 mmol). Themixture was stirred at room temperature for 12 hr. The reaction mixturewas concentrated and the residue was purified by column chromatography(Hexane/AcOEt=2/1, 80 g of silica gel) to provide compound (185) (453mg, 66%) as a white solid.

[0703]¹H NMR (300 MHz, DMSO-d₆) δ 2.41 (3H, s), 2.44 (3H, s), 7.31 (3H,s), 7.49 (1H, d, J=8.7 Hz), 7.61 (1H, s), 7.88-7.91 (2H, m), 8.19 (1H,s), 8.74 (1H, d, J=3.0 Hz), 11.3 (1H, br s), MS (M+H) 541. mp 228-230°.

Example 186 Part 1

[0704] Preparation of 3-chloro-5-fluoro-4-(quinolin-3-yloxy)nitrobenzene(186.1) To a solution of 3,4-Difluoronitrobenzene 1.00 g in conc.H₂SO₄(20 ml), was added portionwise Cl₂O in CCl₄(25 ml, prepared as describedby Cady G. H. et. al in Inorg. Synth. Vol 5, p156 (1957)). The mixturewas stirred at room temperature overnight. The mixture was poured intocrashed ice and extracted with Et₂O (30 ml×3). Combined ether layerswere washed with 10% Na₂SO₃ and brine, and dried over Na₂SO₄. Thesolvent was concentrated to Ca. 10 ml(This solution contains3-Chloro-4,5-difluoronitrobenzene). This solution was diluted withacetone (60 ml), and then 3-hydroxyquinoline 0.75 g and K₂CO₃ 2.2 g wereadded to this solution. The mixture was heated to reflux for 1.5 hr.After cooling the reaction mixture was filtered through a short celitepad. The filtrate was concentrated to give an oil, which was thenpurified by column chromatography (silica gel, AcOEt:Hexane=1:5) toprovide the intermediate compound 186.1 (0.980 g) as a yellow oil.

Part 2

[0705] Preparation of 3-Chloro-5-fluoro-4-(quinolin-3-yloxy)phenylamine(186.2)

[0706] To a solution of3-Chloro-5-fluoro-4-(quinolin-3-yloxy)nitrobenzene (186.1) (0.980 g) andNH₄Cl (1.64 g) in EtOH(50 ml)—H₂O (5 ml), was added iron powder (1.92g). The mixture was heated to reflux for 1 hr. After cooling thereaction mixture was filtered through short celite pad. The filtrate wasconcentrated, diluted with sat. NaHCO₃ and extacted with AcOEt(30 ml×3).The combined organic layeres were washed with brine and dried overNa₂SO₄. Concentration of solvent afford crude product, which waspurified by column chromatography (silicagel, AcOEt:Hexane=1:3) toprovide aniline 186.2 (0.420 g ) as a colorless solid.

Part 3

[0707] Preparation ofN-[3-chloro-5-fluoro-4-(quinolin-3-yloxy)phenyl]-2,4-dichloro-5-methyl-benzenesulfonamide(186)

[0708] To a solution of3-chloro-5-fluoro-4-(quinolin-3-yloxy)phenylamine (186.2) (0.420 g) inpyridine(2.2 ml), was added 2,4-dichloro-5-methylbenzenesulfonylchloride0.360 g. The mixture was stirred at room for 1 hr. The reaction mixturewas purified directly by column chromatography (silicagel,AcOEt:Hexane=1:3). The product was triturated by hexane to give titlecompound (0.522 g). (73%) as a solid.

[0709] NMR(300 MHz/CDCl₃) δ 2.43 (3H, s), 7.05 (1H, d, J=2.6 Hz),7.09-7.11 (1H, m), 7.21 (1H, d, J=2.6 Hz), 7.36 (1H, brs ), 7.49-7.66(4H, m), 7.96 (1H, s), 8.10 (1H, d, J=8.2 Hz), 8.80(1H, br s) MS (M+H)511. mp 187° C.

Example 187

[0710] This illustrates the synthesis of7-chloro-2-(2-fluoro-4-amino-benzyl)-benzoxazole 187.

[0711] To the nitro compound 149 (419 mg, 1.4 mmol) in ethyl acetate (10mL) was added SnCl₂.2H₂O (1.2 g, 5.5 mmol). The reaction mixture washeated to reflux for 30 minutes. After allowing to cool to roomtemperature, the reaction mixture was poured into 13 mL of saturated 2NKOH_((aq)). The layers were separated, and the aqueous layer extracted1×30 mL ethyl acetate. The combined organic layers were washed withsaturated brine and dried over Na₂SO₄. After concentration, the yellowoil was purified by radial chromatography (2 mm silica gel layerChromatatron plate, 3:2 hexanes:ethyl acetate). Eluant containing thedesired product was concentrated to 194 mg of aniline 187.

[0712]¹H NMR (d₆-acetone) δ 7.58 (dd, 1H); 7.39-7.31 (m, 2H); 7.11 (t,1H); 6.50-6.43 (m, 2H); 4.94 (bs, 2H); 4.21 (s, 2H). MS (M+H) 277.1.

Example 188

[0713] This illustrates the synthesis of sulfonamide 188.

[0714] Example 188 A═C═Cl

[0715] Example 189 A═H; C═COMe

[0716] To aniline 187 (95 mg, 0.34 mmol) in acetone (1 mL) was added2,6-lutidine (60 μL, 0.51 mmol) and 2,4-dichloro-benzenesulfonylchloride (93 mg, 0.38 mmol, Maybridge Chemical Co.). After 16 hours, thereaction mixture was filtered through a 1 cm plug of silica gel. Afterconcentration, the yellow oil was purified by radial chromatography (1mm silica gel layer Chromatatron plate, 3:1 hexanes:ethyl acetate).Eluant containing the product was concentrated and the residuerecrystallized from hot hexanes/ethyl acetate. Filtration and dryingunder vacuum yielded the sulphonamide 188 as light yellow crystals (65mg).

[0717]¹H NMR (d₆-acetone) δ 9.70 (bs, 1H); 8.16 (d, 1H); 7.71 (d, 1H);7.60-7.56 (m, 2H); 7.42-7.32 (m, 3H); 7.11-7.09 (m, 2H); 4.32 (s, 2H).MS (M−H) 482.9.

Example 189

[0718] This illustrates the synthesis of sulfonamide 189.

[0719] By the method of Example 188, using the aniline 187 and4-acetyl-benzenesulfonyl chloride compound 189 was obtained as lightyellow crystals.

[0720]¹H NMR (d₆-acetone) δ 9.50 (bs, 1H); 8.11 (d, 2H); 8.11 (d, 2H);7.98 (d, 2H); 7.57 (d, 1H); 7.42-7.32 (m, 3H); 7.12-7.06 (m, 2H); 4.33(s, 2H); 2.61 (s, 3H). MS (M−H): 482.9.

Example 190

[0721] This illustrates the synthesis of compound 190.

[0722] 2-chloro-4-nitro-phenol (2 g, 11.5 mmol) was dissolved in DMF (5mL) and treated with Cs₂CO₃ (3.7 g, 11.5 mmol). The reaction mixture washeated to 50° C. until gas evolution stopped. 2-chlorobenzoxazole (2.65g, 17.3 mmol) was added, and then the reaction mixture was warmed to 75°C. After 5 hours, the heat was removed and the reaction mixture waspoured into 150 mL of deionized water with vigorous stirring. Theprecipitate was collected by filtration and rinsed several times withdistilled water. The product was dried under a stream of air for 15minutes, then under vacuum overnight to afford compound 190 as anoff-white solid (3.4 g), homogeneous by TLC (R_(f)=0.55, 3:1hexanes:ethyl acetate). MS (M+H) 291.0

Example 191

[0723] This illustrates the synthesis of compound 191. See above.

[0724] A round-bottomed flask was charged with 2.01 g (6.93 mmol) ofcompound 190, 50 mL of isopropyl alcohol, and 20 mL of THF. Then 0.5 mLof a 50/50 suspension of Raney Nickel in water was added. The reactionwas then stirred under a hydrogen balloon at room temperature for 24hours. Raney Nickel was removed by filtration through celite, and thesolution was concentrated in vacuo. Recrystallization from ethanol andhexanes gave 1.01 g (60%) of aniline 191 as off-white needles. MS (M+H)261.0.

Example 192

[0725] This illustrates the synthesis of compound 192. (See Table below)

[0726] A round-bottomed flask was charged with aniline 191 (144 mg, 0.55mmol), 2,4-dichlorobenzenesulfonyl chloride (221 mg, 0.55 mmol),2,6-lutidine (97 mg, 0.55 mmol), catalytic DMAP, and acetone (3.0 mL).The reaction was allowed to stir overnight. The reaction was thendiluted with 20 mL of methylene chloride and washed with 10 mL of 1N HCland 10 mL of brine. The organics were dried over Na₂SO₄ and concentratedto a clear oil. This oil was further purified using silica gel flashchromatography. The desired fractions were combined and concentrated toa stiff foam. The product was recrystallized from methylene chloride andhexanes to yield 165 mg (65%) of compound 192 as white crystals.

[0727]¹H NMR (d₆-DMSO) δ 11.21 (1H, s); 8.12 (1H, d, J=8.6 Hz); 7.92(1H, d, J=2.1 Hz); 7.69-7.63 (3H, m); 7.48 (1H, dd, J=7.3, 4.3 Hz);7.31-7.29 (3H, m); 7.18 (1H, dd, J=9.0, 2.6 Hz). MS (M−H) 467.0.

[0728] The additional examples of Table 25 were prepared from aniline191 and the corresponding sulfonyl chloride by the method of Example192. TABLE 25

Example A B C D (M − H) 192 Cl H Cl H 467 193 Cl H Cl Me 481 194 Me H ClMe 195 Cl H CF₃ H 501 196 H H —COMe H 441 197 [2-chloro-5-pyridyl] 434

Example 193

[0729]¹H NMR (d₆-DMSO) δ 11.14 (1H, s); 8.14 (1H, s); 7.87 (1H, s);7.65-7.61 (2H, m); 7.50-7.48 (1H, m); 7.32-7.28 (3H, m); 7.19 (1H, dd,J=8.9, 2.7 Hz); 2.40 (3H, s). MS (M−H) 481.

Example 194

[0730]¹H NMR (d₆-DMSO) δ 10.92 (1H, s); 7.94 (1H, s); 7.65-7.60 (2H, m);7.54 (1H, s); 7.49 (1H, dd, J=4.8,1.6 Hz); 7.31-7.27 (3H, m); 7.16 (1H,dd, J=8.9, 2.6 Hz); 2.56 (3H, s); 2.36 (3H, s).

Example 195

[0731]¹H NMR (d₆-DMSO) δ 11.36 (1H, s); 8.32 (1H, d); 8.18 (1H, s); 7.97(1H, dd); 7.64 (2H, dd); 7.47 (1H, d); 7.31 (3H, m); 7.20 (1H, dd). MS(M−H) 501.

Example 196

[0732]¹H NMR (400 MHz) (d₆-DMSO) δ 10.96 (1H, s); 8.15 (2H, dd); 7.97(2H, d); 7.62 (2H, d); 7.49 (1H, t); 7.31 (3H, m); 7.22 (1H, t); 2.62(3H, s). MS (M−H) 441.0.

Example 197

[0733]¹H NMR (d₆-DMSO) δ 11.04 (1H, s); 8.89 (1H, s); 8.34 (1H, dd);8.05 (1H, d); 7.87 (1H, d); 7.67 (1H, dd); 7.52 (1H, t); 7.38 (1H, d);7.25 (1H, t); 7.19 (1H, t); 2.62 (3H, s). MS (M−H) 434.0.

Example 198

[0734] Preparation of 3-Chloro-4-(quinolin-3-yloxy)nitrobenzene(198) Toa solution of 3-hydroxyquinoline (1.00 g) and3-chloro-4-fluoronitrobenzene (1.21 g) in Acetone(20 ml), was addedK₂CO₃ (2.86 g). The mixture was refluxed for 1 hr. After cooling thereaction mixture was filtered through a short celite pad. The filtratewas concentrated to provide compound 198 (2.07 g, quant.) as a brownoil.

[0735]¹H NMR (300 MHz/CDCl₃) δ 7.02(1H, d, J=9.1 Hz), 7.61(1H, m),7.72-7.80(3H, m), 8.10-8.18 (2H, m), 8.45 (1H, d, J=2.7 Hz), 8.82 (1H,d, J=2.8 Hz).

Example 199

[0736] Preparation of 3-Chloro-4-(quinolin-3-yloxy)phenylamine (199)

[0737] To a solution of nitrobenzene 198 (2.07 g) and NH₄Cl (1.84 g) inEtOH (40 ml)—H₂O (10 ml), was added iron powder (1.92 g). The mixturewas heated to reflux for 1 hr. After cooling the reaction mixture wasfiltered through short celite pad. The filtrate was concentrated,diluted with sat. NaHCO₃ (30 ml) and extacted with AcOEt(30 ml). Thecombined organic layers were washed with brine (30 ml) and dried overNa₂SO₄. Concentration of the solvent afforded the aniline 199 (1.77 g,95%) as a yellow solid.

[0738]¹H NMR(300 MHz/CDCl₃) δ 3.77(2H, br s), 6.63(1H, dd, J=2.7 Hz,J=8.6 Hz), 6.83(1H, d, J=2.7 Hz), 6.99(1H, d, J=8.6 Hz), 7.24(1H, d,J=2.8 Hz), 7.49(1H, m), 7.56-7.64(2H, m), 8.08(1H, m), 8.86(1H, J=2.8Hz).

[0739] The structures for examples 200-208 are illustrated in Table 26.TABLE 26

EXAMPLE V W X Y Z MS(M − H) 200 Cl H Cl H H 372 201 H H H H H 304 203 HCl H H Me 352 204 Cl Cl H Cl H 406 205 Cl H H H Me 354 (M + H) 206 Cl HMe H H 354 (M + H) 207 Cl Cl H H H 372 208 Cl H —SO₂Me H H 416

Example 200

[0740] This illustrates the synthesis of compound 200.

[0741] 2-amino-6-chlorobenzothiazole (3.68 g, 20 mmol) and1,2,3-trichloro-5-nitrobenzene (4.53 g, 20 mmol) were dissolved inanhydrous DMSO (10 mL). Solid K₂CO₃ (3.04 g, 22 mmol) was added and thereaction mixture heated to 150° C. for 4 hours. Let cool, then pouredinto 200 mL deionized water. A fine yellow solid precipitated which wascollected by filtration after attempts to dissolve the product in ethylacetate failed. The yellow solid was suspended in 100 mL of ethylacetate and heated to reflux. After cooling to room temperature,filtration, rinsing with ethyl acetate followed by hexanes, and dryingunder vacuum provided the nitro compound 200 as a yellow powder. (1.06g)

[0742]¹H NMR (d₆-DMSO) δ 8.37 (s, 2H); 7.76 (bs, 1H); 7.30 (dd, 1H);7.23 (bs, 1H). MS (M−H) 372.

Example 201

[0743] This illustrates the synthesis of compound 201.

[0744] To a solution of 2-chloro-4-nitro aniline (2 g) and potassiumt-butoxide (12 mmol) in THF (18 mL) was added a solution of2-chlorobenzothiazole (2.75 g) in THF (6 mL). The mixture was heated atreflux overnight then quenched into water (100 mL). The product isextracted with methylene chloride and purified by flash chromatographyto afford compound 201 (300 mg) as a yellow solid.

[0745]¹H NMR (d6-acetone) δ 9.74 (br s, 1H), 9.214 (br d, 1H), 8.346 (m,2H), 7.891 (d, J=8 Hz, 1H), 7.794 (d, J=8 Hz, 1H), 7.466 (t, J=7.2 Hz,1H), 7.321 (t, J=7.2 Hz, 1H). MS (M−H) 304.

Example 202

[0746] This illustrates the synthesis of compound 202.

[0747] By the method of Abuzar et al, (Ind. J. Chem 20B, 230-233 (1981))2-chloro-4-nitro phenylisothiocyanate (Lancaster) (0.95 g) was coupledwith 2-amino-4-chlorotoluene (0.69 g) in reluxing acetone to form themixed thiourea 202 (1.5 g).

[0748]¹H NMR (DMSO) δ 10.021 (s, 1H), 9.789 (s, 1H), 8.373 (m, 1H),8.197 (m, 2H), 7.441 (d, J=1.6 Hz, 1H), 7.315 (d, J=8.4 Hz, 1H), 7.268(dd, J=8.4, 2. Hz, 1H), 2.237 (s, 3H). MS (M+H) 356. Anal. calcd.:47.20% C, 3.11% H, 11.80% N; found: 47.24% C, 3.15% N, 11.69% N.

Example 203

[0749] This illustrates the synthesis of compound 203.

[0750] To a cool solution of thiourea 202 (0.63 g) in chloroform (6 mL)was added bromine (0.6 g) slowly. The mixture was then heated to refluxfor 2 hours. On cooling, the solids were collected by filtration andthen triturated with acetone to afford benzothiazole 203 as its HBR salt(0.5 g).

[0751]¹H NMR (DMSO) δ 8.989 (br d, J=8.4 Hz, 1H), 8.365 (d, J=2.4 Hz,1H), 8.291 (dd, J=9.2, 2.8 Hz, 1H), 7.259 (m, 2H), 5.4 (br s), 2.557 (s,3H). MS (M−H) 352. Anal. calcd.: for M+0.9HBr: 39.38% C, 2.34% H, 9.84%N; found: 39.44% C, 2.35% H, 9.66% N.

Example 204

[0752] This illustrates the synthesis of compound 204.

[0753] By the method of examples 202 and 203,2,6-dichloro-4-nitrophenylisothiocyanate (GB131780 (1966)) was coupledwith 3,5-dichloroaniline to form the corresponding mixed thiourea whichwas cyclized with bromine to afford benzothiazole 204 suitable for usein the next reaction. MS (M−H) 406

Example 205

[0754] By the method of Example 200, benzothiazole 205 was prepared in78% yield as a yellow solid. MS (M+H) 354.

Example 206

[0755] By the method of Example 200, benzothiazole 206 was prepared in30% yield as a yellow solid. MS (M+H) 354

Example 207

[0756] This illustrates the synthesis of compound 207.

[0757] 2,7-dichlorobenzothiazole (Example 73.2) (0.85 g, 4.2 mmol) and2,6-dichloro-4-nitroaniline (2.1 g, 10.4 mmol) were dissolved inanhydrous DMSO (10 mL). Solid Cs₂CO₃ (4.1 g, 12.5 mmol) was added andthe reaction mixture heated to 80° C. for 16 hours. Let cool, thenpoured into 200 mL DI water. Excess cesium carbonate was neutralizedwith acetic acid. The aqueous layer was extracted 2×100 mL of ethylacetate. The combined organic layers were washed with saturated brine,dried over MgSO₄, filtered, and concentrated to a yellow-brown solid.The insolubility of this compound prevented purification, so the crudematerial was used directly in the next reaction.

[0758]¹H NMR (400 MHz) (d₆-acetone) δ 10.35 (bs, 1H); 8.36 (s, 2H); 7.37(t, 1H); 7.30 (dd, 1H); 7.21 (dd, 1H). MS (M−H) 371.9.

Example 208

[0759] By the method of examples 202 and 203,2,6-dichloro-4-nitrophenylisothiocyanate (GB1131780 (1966)) was coupledwith methyl-(4-aminophenyl)-sulfone to form the corresponding mixedthiourea which was cyclized with bromine to afford benzothiazole 208suitable for use in the next reaction.

[0760]¹H NMR (DMSO) δ 8.44 (s, 2H), 8.28 (br s, 2H), 7.82 (br d, 1H),7.41 (br d, 1H), 3.19 (s, 3H). MS (M−H) 416.

Examples 209-216

[0761] Reduction of the nitro derivatives of Table 26 by the methods ofexample 32 or Example 175 gave the corresponding anilines illustrated inTable 27.

[0762] The structures for examples 209-216 are illustrated in Table 27.TABLE 27

EXAMPLE V W X Y Z MS(M + H) 209 Cl H Cl H H 344 210 H H H H H 276 211 HCl H H Me 324 212 Cl Cl H Cl H 378 213 Cl H H H Me 324 214 Cl H Me H H324 215 Cl Cl H H H 344 216 Cl H —SO₂Me H H 388

Example 209

[0763]¹H NMR (d₆-acetone) δ 8.78 (s, 1H); 7.29 (d, 1H); 7.41 (d, 1H);7.27 (d, 1H); 6.86 (s, 2H); 5.42 (s. 1H). MS (M+H) 344.

Example 212

[0764]¹H NMR (DMSO) δ 10.09 (s, 1H), 7.48 (br s, 1H), 7.31 (d, J=1.8 Hz,1H), 6.72 (s, 2H), 5.91 (br s, 2H). MS (M+H) 378.

Example 215

[0765] Crude 207 was reduced with SnCl₂.2H₂O according to the procedureof Example 32 to afford compound 215 as a greenish/gray solid afterrecrystallization from hot ethyl acetate/hexanes (1.14 g).

[0766]¹H NMR (d₆-acetone) δ 8.87 (bs, 1H); 7.40 (dd, 1H); 7.30 (t, 1H);7.11 (d, 1H); 6.87 (s, 2H); 5.44 (bs, 2H). MS (M+H) 344.0.

Example 216

[0767]¹H NMR (DMSO) δ 10.08 (s, 1H), 8.31 (s, 1H), 7.76 (d, J=8.4 Hz,1H), 7.57 (d, J=8.4 Hz, 1H), 6.73 (s, 2H), 5.90 (s, 2H), 3.17 (s, 3H).MS (M−H) 388.

Examples 217-238

[0768] Sulfonation of the anilines of Table 27 by the methods of example3 or 192 provides the compounds illustrated in Table 28. TABLE 28

Ex- am- MS ple (M − # A B C D V W X V Z H) 217 Cl H Cl Me Cl H Cl H H564 218 Cl H Cl H Cl H Cl H H 550 219 Cl H CF₃ H Cl H Cl H H 584 220 ClH Cl H H H H H H 482 221 Cl H CF₃ H H H H H H 516 222 Cl H Cl Me H H H HH 496 223 Cl H Cl H Cl H Cl H Me 530 224 Cl H CF₃ H Cl H Cl H Me 564 225Cl H Cl H Cl Cl H Cl H 584 226 Cl H CF₃ H Cl Cl H Cl H 618 227 Cl H ClMe Cl Cl H Cl H 598 228 Cl H Cl H Cl H H H Me 530 229 Cl H CF₃ H Cl H HH Me 564 230 Cl H Cl Me Cl H H H Me 544 231 H H —COMe H Cl H H H Me —232 Cl H Cl H Cl H Me H H 530 233 Cl H CF₃ H Cl H Me H H 564 234 Cl H ClMe Cl H Me H H 544 235 Cl H Cl H Cl Cl H H H 550 236 Cl H CF₃ H Cl Cl HH H 584 237 Cl H Cl H Cl H —SO₂Me H H 594 238 Cl H CF₃ H Cl H —SO₂Me H H628

Example 217

[0769]¹H NMR (d₆-acetone) δ 9.19 (bs, 1H); 8.51 (s, 1H); 7.74 (d, 1H);7.72 (s, 1H); 7.43 (s, 2H); 7.37 (d, 1H); 7.28 (dd, 1H); 2.46 (s, 3H).MS (M−H) 563.9.

Example 218

[0770]¹H NMR (d₆-acetone) δ 9.19 (bs, 1H); 8.22 (d, 1H); 7.78 (d, 1H);7.74 (d, 1H); 7.67 (dd, 1H); 7.43 (s, 2H); 7.37 (d, 1H); 7.28 (dd, 1H).MS (M−H) 549.8.

Example 219

[0771]¹H NMR (d₆-acetone) δ 10.05 (bs, 1H); 9.22 (bs, 1H); 8.45 (d, 1H);8.06 (s, 1H); 7.98 (d, 1H); 7.73 (m, 1H); 7.45 (s, 2H); 7.36 (d, 1H);7.28 (dt, 1H). MS (M−H) 583.8.

Example 223

[0772]¹H NMR (DMSO) δ 10.96 (1H, s), 10.11 (1H, s), 8.12-8.22 (1H,broad), 8.06 (1H, d, 8.6), 7.90 (1H, d, J=2.1 Hz), 7.65 (1H, dd, J=8.6,2.1 Hz), 7.23 (1H, d, J=3.5 Hz), 7.10-7.20 (3H, m), 2.44 (3H, s). MS(M−H) 529.8

Example 224

[0773]¹H NMR (DMSO) δ 11.11 (1H, s), 10.11 (1H, s), 8.27 (1H, d, J=8.0Hz), 8.16 (2H, s), 7.94 (1H, d, J=8.6 Hz), 7.10-7.26 (4H, m), 2.43 (3H,s). MS (M−H) 563.9. mp 192.6° C.

Example 225

[0774]¹H NMR (DMSO) δ 11.49 (s, 1H), 10.44 (s, 1H), 8.164 (d, J=8.4 Hz,1H) 7.95 (d, J=2 Hz, 1H), 7.71 (dd, J=8.4, 2 Hz, 1H), 7.50 (br s, 1H),7.35 (d, J=1.6 Hz, 1H), 7.25 (s, 2H). MS (M−H) 584.

Example 226

[0775]¹H NMR(DMSO) δ 11.59 (s, 1H), 10.40 (s, 1H), 8.368 (d, J=8.4 Hz,1H), 8.20 (br s, 1H), 8.00 (br d, J=8.4 Hz, 1H), 7.48 (br s, 1H), 7.344(t, J=1.6 Hz, 1H), 7.274 (d, J=1.6 Hz, 2H). MS (M−H) 618.

Example 227

[0776]¹H NMR (DMSO) δ 11.37 (s, 1H), 10.40 (s, 1H), 8.19 (br s, 1H),7.90 (m, 1H), 7.53 (br s, 1H), 7.35 (br s, 1H), 7.25 (br s, 2H), 2.415(s, 3H). MS (M−H) 598.

Example 228

[0777]¹H NMR (d₆-DMSO) δ 11.44 (1H, broad s); 9.96 (1H, broad s); 8.33(1H, d); 8.19 (1H, s); 7.99 (1H, dd); 7.43 (1H, broad s); 7.26 (2H, s);7.07 (1H, d); 6.97 (1H, t); 2.35 (3H, s). MS (M−H) 529.9.

Example 229

[0778]¹H NMR(d₆-DMSO) δ 11.26 (1H, broad s); 9.96 (1H, broad s); 8.12(1H, d); 7.93 (1H, d); 7.69 (1H, dd); 7.43 (1H, broad s); 7.23 (2H, s);7.08 (1H, d); 6.97 (1H, t); 2.36 (3H, s). MS (M−H) 564.

Example 230

[0779]¹H NMR (d₆-DMSO) δ 11.23 (1H, broad s); 9.96 (1H, broad s); 8.14(1H, s); 7.88 (1H, s); 7.43 (1H, broad s); 7.24 (2H, s); 7.08 (1H, d);6.97 (1H, t); 2.40 (3H, s); 2.36 (3H, s). MS (M−H) 543.9.

Example 231

[0780]¹H NMR (d₆-DMSO) δ 11.02 (1H, broad s); 9.96 (1H, broad s); 8.16(2H, d); 7.97 (2H, d); 7.43 (1H, broad s); 7.26 (1H, s); 7.07 (1H, d);6.97 (1H, t); 2.62 (3H, s); 2.36 (3H, s).

Example 232

[0781]¹H NMR (d₆-DMSO) δ 11.28 (1H, broad s); 9.79 (1H, broad s); 8.13(1H, d); 7.93 (2H, d); 7.70 (1H, dd); 7.44 (1H, broad s); 7.21 (3H, s);7.05 (1H, d); 2.03 (3H, s). MS (M−H) 529.9.

Example 233

[0782]¹H NMR (d₆-DMSO) δ 11.43 (1H, broad s); 9.79 (1H, broad s); 8.34(1H, d); 8.19 (1H, s); 7.99 (1H, d); 7.44 (1H, broad s); 7.24 (3H, s);7.04 (1H, d); 2.30 (3H, s). MS (M−H) 564.

Example 234

[0783]¹H NMR (d₆-DMSO) δ 11.22 (1H, broad s); 9.79 (1H, broad s); 8.15(1H, s); 7.89 (1H, s); 7.44 (1H, broad s); 7.23 (3H, s); 7.04 (1H, d);2.41 (3H, s); 2.31 (3H, s). MS (M−H) 543.9.

Example 235

[0784]¹H NMR (d₆-acetone) δ 9.92 (bs, 1H); 9.35 (bs, 1H); 8.23 (d, 1H);7.78 (d, 1H); 7.67 (dd, 1H); 7.45 (s, 2H); 7.36-7.29 (m, 2H); 7.16 (dd,1H). MS (M−H) 549.

Example 236

[0785]¹H NMR (d₆-acetone) δ 8.45 (d, 1H); 8.06 (s, 1H); 7.97 (d, 1H);7.46 (s, 2H); 7.33-7.29 (m, 2H); 7.16 (dd, 1H). MS (M−H) 583.8.

Example 237

[0786]¹H NMR (DMSO) δ 11.43 (br s, 1H), 10.40 (br s, 1H), 8.33 (br s,1H), 8.16 (d, J=8 Hz, 1H); 7.94 (d, J=2 Hz, 1H), 7.753 (dd, J=8.2, 2 Hz,1H), 7.71 (dd, J=8.4, 2 Hz, 1H),7.55 (br s, 1H), 7.265 (s, 2H), 3.22 (s,3H). MS (M−H) 594.

Example 238

[0787]¹H NMR (DMSO) δ 11.55 (br s, 1H), 10.40 (br s, 1H), 8.38 (m, 2H),8.22 (br s, 1H), 8.02 (br d, 1H), 7.77 (dd, J=8.4, 2 Hz, 1H), 7.55 (brs, 1H), 7.295 (s, 2H), 3.19 (s, 3H). MS (M−H) 628. TABLE 29

Example # A X Y yield 239 SH H CF₃ 92% 240 SH H CO₂H 66% 241 SH CN H 97%243 SH H CN 49% 245 SH H Me 53% 250 Cl H Cl 96%

Example 239

[0788] 2-Mercapto-5-trifluoromethyl-benzothiazole (239)

[0789] In analogy to the procedure of Chaudhuri, N. Synth. Commun. 1996,26, 20, 3783, O-ethylxanthic acid, potassium salt (Lancaster, 7.5 g,46.9 mmol) was added to a solution of2-bromo-5-trifluoromethylphenylamine (Aldrich, 5.0 g, 20.8 mmol) inN,N-dimethylformamide (DMF, 30 mL). The mixture was heated to reflux for4 hours. After cooling to room temperature, the mixture was poured intoice water and acidified with 2N HCl. The solid product was collected byfiltration. Recrystalization from CHCl₃/Hexanes gave 239 (4.5 g, 92%) asa white solid.

[0790]¹H NMR (400 MHz, DMSO-d₆) δ 14.00 (s, 1H), 7.94 (d, J=8.1 Hz, 1H),7.62 (dd, J=8.4, 1.0 Hz, 1H), 7.48 (d, J=1.0 Hz, 1H). MS (M−H) 234.

Example 240

[0791] 2-Mercapto-benzothiazol-5-carboxylic acid (240)

[0792] 2-Mercapto-benzothiazol-5-carboxylic acid (240) (3.5 g, 66%) wassynthesized from 4-chloro-3-nitro-benzoic acid, obtained from Fluka, andpotassium dithiocarbonate O-ethyl ester, obtained from Lancaster,according to the procedure of Chaudhuri, N. Synth. Commun. 1996,26, 20,3783.

[0793]¹H NMR (400 MHz, DMSO-d₆) δ 14.0 (s, 1H), 13.3 (bs, 1 H),7.85-7.79 (m, 3 H).

Example 241

[0794] 2-Mercapto-benzothiazole-6-carbonitrile (241)

[0795] The title compound was prepared using the method of Example 239,starting with 4-amino-3-chloro-benzonitrile (Lancaster, 5.0 g, 32.7mmol), O-ethylxanthic acid, potassium salt, (Lancaster, 11.8 g, 73.7mmol) in DMF (40 mL). The mercaptobenzothiazole (241) (6.1 g, 97%) wasobtained as a pale brown solid.

[0796]¹H NMR (DMSO-d₆) δ 14.10 (s, 1H), 8.22 (d, J=1.3 Hz, 1H), 7.82(dd, J=8.4, 1.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H). MS (M−H) 191.

Example 242

[0797] 3-Amino-4-chloro-benzonitrile (242)

[0798] The title compound was prepared using the method of Example 32,starting with 4-chloro-3-nitro-benzonitrile (Fluka, 11.0 g, 60 mmol),tin chloride dihydrate (Aldrich, 67.8 g, 300 mmol). 9.0 g (98%) of crudecompound 242 was obtained as a yellowish solid.

[0799]¹H NMR (DMSO-d₆) δ 7.39 (d, J=8.1 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H),6.93 (dd, J=8.2, 2.0 Hz, 1H), 5.88 (s, 2H). MS (M−H) 151.

Example 243

[0800] 2-Mercapto-benzothiazole-5-carbonitrile (243)

[0801] The title compound was prepared using the method of Example 239,starting with 3-amino-4-chloro-benzonitrile (242) (9.0 g, 59.0 mmol),O-ethylxanthic acid, potassium salt (Lancaster, 21.23 g, 132.7 mmol) inDMF (90 mL). 5.6 g (49%) of compound 243 was obtained as a pale brownsolid.

[0802]¹H NMR (DMSO-d₆) δ 14.10 (br s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.70(dd, J=8.3, 1.1 Hz, 1H), 7.60 (br s, 1H). MS (M−H) 191.

Example 244

[0803] 2-Bromo-5-methyl-phenylamine (244)

[0804] The title compound was prepared using the method of Example 32,starting with 1-bromo-4-methyl-2-nitro-benzene (Lancaster, 10.1 g, 46.7mmol), tin chloride dihydrate (Aldrich, 52.8 g, 233 mmol). 8.2 g (94%)of crude compound 244 was obtained as a pale brown oil.

[0805]¹H NMR (DMSO-d₆) δ 7.18 (d, J=8.1 Hz, 1H), 6.60 (d, J=2.1 Hz, 1H),6.93 (dd, J=8.1, 1.8 Hz, 1H), 5.34 (s, 2H), 2.26 (s, 3H). MS (M+H)186.

Example 245

[0806] 2-Mercapto -5-Methyl-benzothiazole (245)

[0807] The title compound was prepared using the method of Example 239,starting with 2-bromo-5-methyl-phenylamine (244) (4.48 g, 24.0 mmol),O-ethylxanthic acid, potassium salt (Lancaster, 8.70 g, 54 mmol) in DMF(35 mL). The mercaptobenzothiazole 245 was obtained as an pale brownsolid (2.31 g, 53%).

[0808]¹H NMR (DMSO-d₆) δ 13.70 (br s, 1H), 7.56 (d, J=8.6 Hz, 1H),7.15-7.10 (m, 2H), 2.38 (s, 3H). MS (M−H) 180.

Example 246 & 247

[0809] 2,3-Dichloro-5-nitrobenzoic Acid (246)

[0810] 2,3-Dichlorobenzoic acid, obtained from Aldrich, (40 g, 0.21mole) was added portion wise to a −20° C. concentrated H₂SO₄, obtainedfrom Acros, (233 mL) solution which was fitted with a mechanicaloverhead stirrer. During the addition process, a separate flaskcontaining concentrated H₂SO₄ (50 mL) was cooled to 0° C. and fumingHNO₃, obtained from Acros, (16.6 mL) was slowly added. This solution wasthen added dropwise to the 2,3-Dichlorobenzoic acid solution at a ratewhich kept the reaction mixture at or slightly below −15° C. After theaddition was complete the resulting solution was allowed to warm to 10°C. over 3 hours. The crude solid material was filtered through a frittedfilter funnel, washed with cold H₂O (200 mL), and dried under a streamof air followed by high vacuum to yield 21.7 g (44%) of product (246)which contained 4% of the undesired regioisomer(2,3-Dichloro-6-nitrobenzoic acid 247) based on ¹H NMR analysis. Thefiltrate was slowly poured over ice and additional solid precipitated.This solid was observed to be a 3:1 mixture of2,3-dichloro-6-nitrobenzoic acid (247) to 2,3-dichloro-5-nitrobenzoicacid (246) based on ¹H NMR analysis.

[0811] 2,3-Dichloro-5-nitrobenzoic acid (246): ¹H NMR (DMSO-d₆) δ 8.63(d, J=2.7 Hz, 1H), 8.47 (d, J=2.7 Hz, 1H). 2,3-Dichloro-6-nitrobenzoicacid: (247). ¹H NMR (DMSO-d₆) δ 8.22 (d, J=9.0 Hz, 1H), 8.02 (d, J=9.0Hz, 1H).

Example 248

[0812] 1-(2,3-Dichloro-5-nitro-phenyl)-ethanone (248)

[0813] To thionyl chloride, obtained from Aldrich, (125 mL) at 0° C. wasslowly added 2,3-Dichloro-5-nitrobenzoic acid (246) (21.7 g, 91.9 mmol).The ice bath was taken away and the resulting solution was heated toreflux for 17 hours (note: acid completely dissolves upon heating).After cooling to ambient temperature, the excess thionyl chloride wasremoved under vacuum and the resulting acid chloride was allowed tostand under high vacuum for 15 h and used in the next step withoutfurther purification. To a 1M solution of NaH, 60% oil dispersionobtained from Aldrich, (11.39 g, 285 mmol) in DMF at 0° C. was slowlyadded diethylmalonate, obtained form Aldrich, (14.65 mL, 96.5 mmol)dropwise and the resulting solution was allowed to stir for 30 minutes.The acid chloride was dissolved in DMF (184 mL) and slowly added viacannula to the reaction mixture. The resulting solution was then allowedto stir for 16 h as ambient temperature was reached followed byrecooling to 0° C. and slowly quenching with excess 2M aqueous HCl (200mL). To the crude reaction was added H₂O (500 mL) and EtOAc (500 mL).The aqueous layer was extracted three times with EtOAc (500 mL), theorganic layers were combined, washed four times with saturated aqueousbrine (500 mL), dried over Na₂SO₄, and concentrated under vacuum toyield an oil which was used in the next step without furtherpurification. The resulting product was dissolved in 111 mL of a 7.7/5/1AcOH/H₂O/conc. H₂SO₄, solution and heated to reflux for 22 hours. TheAcOH was removed under vacuum followed by EtOAc addition (200 mL). Thesolution was neutralized using 2M aqueous NaOH, extracted 3 times withEtOAc (200 mL). The combined organic layers were washed twice withsaturated aqueous brine (200 mL), dried over Na₂SO₄, and concentratedunder reduced pressure. The crude material was purified by columnchromatography (30% CH₂Cl₂ in hexane) to yield 17.6 g (82%) of ketone248 as a light brown solid.

[0814]¹H NMR (DMSO-d₆) δ 8.61 (d, J=2.6 Hz, 1H), 8.48 (d, J=2.6 Hz, 1H),2.65 (s, 3H).

Example 249

[0815] 2-Methoxy4-nitrobenzenethiol (249)

[0816] 2-Methoxy-4-nitrobenzenethiol (249) was prepared according to themethod of Price and Stacy, J. Amer. Chem. Soc. 68, 498-500 (1946)) in67% yield from 1-chloro-2-methoxy-4-nitro-benzene, obtained fromAldrich._.

[0817]¹H NMR (DMSO-d₆) δ 7.8 (bd, J=8.4 Hz, 1H), 7.73 (bs, 1H), 7.62(bd, J=8.4 Hz, 1H), 5.8 (bs, 1H), 3.95 (s, 3H). MS (M−H) 184.

Example 250

[0818] 2,5-Dichloro-benzenethiazole (250)

[0819] 5-Chloro-benzenethiazole-2-thiol, obtained from Aldrich, (2 g,9.9 mmol) was added slowly to sulfuryl chloride, obtained from Aldrich,(20 mL) and stirred for 1 h followed by heating to 50° C. for 15minutes. The mixture was cooled, poured slowly over ice water andstirred for 30 minutes. The product precipitated out of solution as ayellow solid and was collected by vacuum filtration and dried under astream of air followed by high vacuum to give 1.92 g (96%) of compound250.

[0820]¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=8.7 Hz, 1H), 8.1 (d, J=2.0,1H), 7.59 (dd, J=8.7, 2.1 Hz, 1H). TABLE 30 Table 30 illustrates thestructures of examples 251-264.

# X V W Yield 251 5-Cl Cl —COMe 52% 252 5-CF₃ Cl H 92% 253 5-CO₂H Cl H66% 254 5-CO₂Me Cl H 100%  255 5-CO₂H Cl Cl 100%  256 5-CO₂Me Cl Cl100%  257 5-Cl H —OMe 75% 258 5-CF₃ Cl Cl 99% 259 5-CF₃ Cl —COMe 75% 2606-CN Cl Cl 99% 261 6-CN Cl H 93% 262 5-CN Cl Cl 99% 263 5-CN Cl H 92%264 5-Me Cl —COMe 98%

Example 251

[0821]1-[3-Chloro-2-(5-chloro-benzothiazol-2-ylsulfanyl)-5-nitro-phenyl]-ethanone(251)

[0822] To a 0.55M solution of 5-chloro-2-mercaptobenzothiazole, obtainedfrom Aldrich, (5.55 g, 27.5 mmol) in DMF at ambient temperature wasadded NaH, 60% oil dispersion obtained from Aldrich, (1.2 g, 30.0 mmol)portionwise followed by 1-(2,3-Dichloro-5-nitro-phenyl)-ethanone (248)(5.83 g, 25 mmol). The reaction solution turned from bright orange todeep red upon acetophenone addition and was heated to 60° C. for 1 hour.The mixture was allowed to cool for a couple of minutes and the productwas precipitated out of solution by the slow addition of H₂O (250 mL).After 1 h of stirring the product was collect by vacuum filtration usinga buchner funnel, dried under a stream of air for 3 h, and triteratedwith a 1:1 MeOH/CH₂Cl₂ solution (200 mL) to yield 5.2 g (52%) of 251 asan orange solid. An additonal 3.77 g (39%) could be isolated bypurifying the mother liquor using column chromatography (dry load,100%CH₂Cl₂).

[0823]¹H NMR (DMSO-d₆) δ 8.68 (d, J=2.5 Hz, 1H), 8.6 (d, J=2.4 Hz, 1H),8.05 (d,=8.6 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.56 (dd, J=8.6, 2.0 Hz,1H) 2.65 (s, 3H).

Example 252

[0824]2-(2-Chloro-4-nitro-phenylsulfanyl)-5-trifluoromethyl-benzothiazole(252)

[0825]2-(2-Chloro-4-nitro-phenylsulfanyl)-5-trifluoromethyl-benzothiazole(252) was prepared (92%) from 2-chloro-1-fluoro-4-nitrobenzene, obtainedfrom Aldrich, and 5-trifluoromethyl-benzothiazol-2-thiol (239) in asimilar manner as described in example 251.

[0826]¹H NMR (DMSO-d₆) δ 8.58 (d, J=2.4 Hz, 1H), 8.38-8.32 (m, 2 H),8.05 (d,=8.6 Hz, 1H), 8.28 (dd, J=8.7, 2.5 Hz, 1H), 8.09 (d, J=8.7 Hz,1H), 7.8 (bd, J=9.9 Hz, 1H).

Example 253

[0827] 2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazol-5-carboxylicAcid (253)

[0828] 2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazol-5-carboxylicacid was prepared (66%) from 2-mercapto-benzothiazol-5-carboxylic acid(240) and 2-chloro-1-fluoro-4-nitrobenzene, obtained from Aldrich, in asimilar manner as described in

Example 251.

[0829]¹H NMR (DMSO-d₆) δ 8.56 (d, J=2.4 Hz, 1H), 8.42 (bs, 1 H), 8.27(dd,=8.7, 2.4 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H),8.0 (dd, J=8.4, 1.4 Hz, 1H). MS (M−H) 365.

Example 254

[0830] 2-(2-Chloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carboxylicacid methyl ester (254)

[0831] To a 0.25M solution of2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazol-5-carboxylic acid(253), (1.38 g, 3.8 mmol) in 10% MeOH in THF was added a 2M solution of(trimethylsilyl)diazomethane in hexane, obtained from Aldrich, (2.1 mL,4.18 mmol) and the resulting solution was allowed to stir for 18 hours.The crude reaction mixture was concentrated under vacuum to yield 1.4 g(100%) of ester 254 which was taken on without further purification.

[0832]¹H NMR (DMSO-d₆) δ 8.6 (d, J=2.5 Hz, 1H), 8.45 (d, J=1.4 Hz, 1 H),8.28 (dd,=8.7, 2.5 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.1 (d, J=8.7 Hz,1H), 8.0 (dd, J=8.4, 1.4 Hz, 1H), 3.9 (s, 3H).

Example 255

[0833]2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carboxylic acid(255)

[0834]2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carboxylic acid(255) was prepared (100%) from 2-mercapto-benzothiazol-5-carboxylic acid(240) and 1,2,3-trichloro-5-nitrobenzene, obtained from Aldrich, in asimilar manner as described in example 251.

[0835]¹H NMR (DMSO-d₆) δ 11.2 (bs, 1 H), 8.6 (s, 2H), 8.31 (d, J=1.4 Hz,1H), 8.13 (d, J=8.4 Hz, 1H), 7.94 (dd, J=8.5, 1.4 Hz, 1H). MS (M−H) 399.

Example 256

[0836]2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carboxylic acidmethyl ester (256)

[0837]2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carboxylic acidmethyl ester (256) was prepared (100%) from2-(2,6-dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carboxylic acid255 in a similar manner as described in Example 254.

[0838]¹H NMR (400 MHz, DMSO-d₆) δ 8.6 (s, 2H), 8.33 (d, J=1.6 Hz, 1H),8.16 (d, J=8.5 Hz, 1H), 7.95 (dd, J=8.4, 1.6 Hz, 1H), 3.9 (s, 3H).

Example 257

[0839] 5-Chloro-2-(2-methoxy-4-nitro-phenylsulfanyl)-benzothiazole (257)

[0840] 5-Chloro-2-(2-methoxy-4-nitro-phenylsulfanyl)-benzothiazole (257)was prepared (75%) from 2-methoxy-4-nitrobenzenethiol (249) and2,5-dichlorobenzothiazole (250), in a similar manner as described inexample 251.

[0841]¹H NMR (DMSO-d₆) δ 8.05 (bd, J=8.6 Hz, 1H), 8.03 (d, J=2.0, 1H),7.99-7.94 (m, 3H), 7.48 (dd, J=8.6, 2.1 Hz, 1H), 3.95 (s, 3H).

Example 258

[0842]2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-5-trifluoromethyl-benzothiazole(258)

[0843] To a solution of 2-mercapto-5-trifluoromethyl-benzothiazole (239)(470 mg, 2.0 mmol) in DMF (20 mL) was added NaH (Aldrich, 60% suspensionin hexanes, 80 mg, 2.0 mmol). After the resulting mixture was stirred atambient temperature for 20 minutes, was added1,2,3-trichloro-5-nitrobenzene (Acros, 452 mg, 2.0 mmol). The mixturewas then heated at 60° C. for 4 hours. After cooled to room temperature,the mixture was poured to water and stirred for 1 hour. The solidproduct was collected by vacuum filtration to give 258 as a pale yellowsolid (840 mg, 99%) which was used in the next reaction without furtherpurification.

[0844]¹H NMR (DMSO-d₆) δ 8.61 (s, 2H), 8.27 (d, J=8.4 Hz, 1H), 7.21 (brs, 1H), 7.74 (dd, J=8.4,1.5 Hz, 1H). MS (M+H) 425.

Example 259

[0845]1-[3-Chloro-5-nitro-2-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone(259)

[0846] The title compound was prepared using the method of Example 258,starting with 5-trifluoromethyl-benzothiazole-2-thiol (239) (470 mg, 2.0mmol), 1-(2,3-dichloro-5-nitro-phenyl)-ethanone (248) (466 mg, 2.0 mmol)and NaH (Aldrich, 60% suspension, 80 mg, 2.0 mmol) in DMF (20 mL).Compound 259 (750 mg, 87%) was obtained as a yellow solid.

[0847]¹H NMR (DMSO-d₆) δ 8.68 (d, J=2.6 Hz, 1H), 8.62 (d, J=2.5 Hz, 1H),8.27 (d, J=8.4 Hz, 1H), 8.20 (br s, 1H), 7.74 (dd, J=8.5, 1.7 Hz, 1H),2.65 (s, 3H) MS (M+H) 433.

Example 260

[0848]2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-benzothiazole-6-carbonitrile(260)

[0849] The title compound was prepared using the method of example 258,starting with 2-mercapto-benzothiazole-6-carbonitrile (241) (960 mg, 5.0mmol), 1,2,3-trichloro-5-nitrobenzene (Acros, 1.13 g, 5.0 mmol) and NaH(Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 260(1.9 g, 99%) was obtained as a yellow solid.

[0850]¹H NMR (DMSO-d₆) δ 8.61 (s, 2H), 8.58 (d, J=1.8 Hz, 1H), 7.99 (d,J=8.5 Hz, 1H), 7.88 (dd, J=8.5, 1.8 Hz, 1H).

Example 261

[0851] 2-(2-Chloro-4-nitro-phenylsulfanyl)-benzothiazole-6-carbonitrile(261)

[0852] The title compound was prepared using the method of example 258,starting with 2-mercapto-benzothiazole-6-carbonitrile (241) (960 mg, 5.0mmol), 2-chloro-1-fluoro-4-nitrobenzene (Aldrich, 878 mg, 5.0 mmol) andNaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound261 (1.62 g, 93%) was obtained as a yellow solid.

[0853]¹H NMR (DMSO-d₆) δ 8.62 (d, J=1.5 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H),8.29 (dd, J=8.6, 2.4 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 8.06 (d, J=8.6 Hz,1H), 7.91 (dd, J=8.5, 1.6 Hz, 1H). MS (M+H) 348.

Example 262

[0854]2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carbonitrile(262)

[0855] The title compound was prepared using the method of example 258,starting with 2-mercapto-benzothiazole-5-carbonitrile (243) (960 mg, 5.0mmol), 1,2,3-trichloro-5-nitrobenzene (Acros, 1.13 g, 5.0 mmol) and NaH(Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 262(1.9 g, 99%) was obtained as a yellow solid.

[0856]¹H NMR (DMSO-d₆) δ 8.62 (s, 2H), 8.38 (d, J=1.2 Hz, 1H), 8.24 (d,J=8.4 Hz, 1H), 7.88 (dd, J=8.4, 1.5 Hz, 1H).

Example 263

[0857] 2-(2-Chloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carbonitrile(263)

[0858] The title compound was prepared using the method of Example 258,starting with 2-mercapto-benzothiazole-5-carbonitrile (243) (960 mg, 5.0mmol), 2-chloro-1-fluoro-4-nitrobenzene (Aldrich, 878 mg, 5.0 mmol) andNaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound263 (1.60 g, 92%) was obtained as a yellow solid.

[0859]¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (d, J=2.4 Hz, 1H), 8.49 (d, J=1.2Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.29 (dd, J=8.7, 2.5 Hz, 1H), 8.12 (d,J=8.7 Hz, 1H), 7.85 (dd, J=8.5, 1.5 Hz, 1H). MS (M+H) 348.

Example 264

[0860]1-[3-Chloro-2-(5-methyl-benzothiazol-2-ylsulfanyl)-5-nitro-phenyl]-ethanone(264)

[0861] The title compound was prepared using the method of example 258,starting with 5-methyl-benzothiazole-2-thiol (245) (1.90 g, 10.5 mmol),1-(2,3-dichloro-5-nitro-phenyl)-ethanone (248) (2.45 g, 10.5 mmol) andNaH (Aldrich, 60% suspension, 420 mg, 10.5 mmol) in DMF (20 mL).Compound 264 (3.87 g, 98%) was obtained as a yellow solid.

[0862]¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.5Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.67 (br s, 1H), 7.24 (dd, J=8.2, 1.5Hz, 1H), 2.65 (s, 3H), 2.41 (s, 3H). MS (M+H) 379.

[0863] Examples 265-276: Reduction of the compounds of Table 30 providesthe compounds illustrated in Table 31. TABLE 31 Table 31 illustrates thestructures of examples 265-276

# X V V W Yield 265 H Cl Cl COMe 83% 266 H CF₃ Cl H 97% 267 H CO₂Me Cl H96% 268 H CO₂Me Cl Cl 93% 269 H Cl H OMe 100%  270 H CF₃ Cl Cl 96% 271 HCF₃ Cl COMe 100%  272 CN H Cl Cl 98% 273 CN H Cl H 93% 274 H CN Cl Cl80% 275 H CN Cl H 93% 276 H Me Cl COMe 68%

Example 265

[0864]1-[5-Amino-3-chloro-2-(5-chloro-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone(265)

[0865] To a 0.14M solution of1-[3-Chloro-2-(5-chloro-benzothiazol-2-ylsulfanyl)-5-nitro-phenyl]-ethanone(251)(4.08 g, 10.26 mmol) in a 2:2:1 solution of EtOH, obtained fromgold shield,:THF, obtained from Aldrich,:H₂O was added NH₄ ⁺Cl⁻,obtained from Aldrich, (2.74 g, 51.29 mmol) followed by iron(0) powder,obtained from Aldrich, (2.86 g, 51.29 mmol). The resulting solution washeated to reflux for 2.5 h with vigorous stirring. TLC and mass spectralanalysis showed starting material and hydroxyl amine intermediate so anadditional 5 Eq. of both NH₄ ⁺Cl⁻and iron powder were subsequently addedand the reaction mixture was allowed to continue to reflux for anadditional 1.75 hours. The hot solution was immediately filtered througha plug of celite and the celite was washed with copious amounts ofEtOAc. The organic layer was concentrated under vaccum, resuspended inEtOAc (100 mL) and NaHCO₃ (100 mL),and extracted 3 times with EtOAc (100mL). The organic layer was washed twice with saturated aqueous brine(100 mL), dried over Na₂SO₄, concentrated under vacuum, and purified bycolumn chromatography (10-50% EtOAc in hexane) to yield compound 265(3.14 g, 83%) as a yellow solid.

[0866]¹H NMR (DMSO-d₆) δ 7.95 (d, J=8.6 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H),7.39 (dd, J=8.6, 2.1 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 6.72 (d, J=2.4 Hz,1H), 6.41 (s, 2H), 2.45 (s, 3H). MS (M+H) 369.

Example 266

[0867] 3-Chloro4-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenylamine (266)

[0868]3-Chloro-4-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenylamine(266) was prepared (97%) from2-(2-Chloro-4-nitro-phenylsulfanyl)-5-trifluoromethyl-benzothiazole(252), in a similar manner as described in example 90.

[0869]¹H NMR (DMSO-d₆) δ 8.2-8.12 (m, 2 H), 7.65 (dd, J=8.5, 1.7 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 6.9 (d, J=2.4 Hz, 1H), 6.7 (dd, J=8.5, 2.4Hz, 1H) 6.25 (bs, 2H).). MS (M−H) 359.

Example 267

[0870] 2-(4-Amino-2-chloro-phenylsulfanyl)-benzothiazole-5-carboxylicacid methyl ester (267)

[0871] 2-(4-Amino-2-chloro-phenylsulfanyl)-benzothiazole-5-carboxylicacid methyl ester (267) was prepared (96%) from2-(2-Chloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carboxylic acidmethyl ester (254) by the method of example 90.

[0872]¹H NMR (DMSO-d₆) δ 8.3 (d, J=1.6 Hz, 1H), 8.05 (d, J=8.4 Hz, 1 H),7.88 (dd,=8.4, 1.6 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 6.89 (d, J=2.4 Hz,1H), 6.65 (dd, J=8.5, 2.4 Hz, 1H) 3.9 (s, 3H). MS (M−H) 349.

Example 268

[0873]2-(4-Amino-2,6-dichloro-phenylsulfanyl)-benzothiazole-5-carboxylic acidmethyl ester(268)

[0874]2-(4-Amino-2,6-dichloro-phenylsulfanyl)-benzothiazole-5-carboxylic acidmethyl ester (268) was prepared (93%) from2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carboxylic acidmethyl ester (256) in a similar manner as described in example 90.

[0875]¹H NMR (DMSO-d₆) δ 8.34 (d, J=1.2 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H),7.93 (dd, J=8.4, 1.6 Hz, 1H), 6.9 (s, 2H), 6.5 (s, 2H), 3.9 (s, 3H). MS(M−H) 383.

Example 269

[0876] 4-(5-Chloro-benzothiazol-2-ylsulfanyl)-3-methoxy-phenylamine(269)

[0877] 4-(5-Chloro-benzothiazol-2-ylsulfanyl)-3-methoxy-phenylamine(269) was prepared (100%) from5-chloro-2-(2-methoxy-4-nitro-phenylsulfanyl)-benzothiazole (257), bythe method of example 265.

[0878]¹H NMR (400 MHz, DMSO-d₆) δ 7.9 (d, J=8.5 Hz, 1H), 7.85 (d, J=2.0,1H), 7.34 (dd, J=8.5, 2.0 Hz, 1H), 7.3 (d, J=8.3 Hz, 1H), 6.39 (d, J=2.0Hz, 1H), 6.29 (dd, J=8.3, 2.1 Hz, 1H), 5.93 (s, 2H), 3.7 (s, 3H). MS(M+H) 323.

Example 270

[0879]3,5-Dichloro-4-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenylamine(270)

[0880] To a solution of2-(2,6-dichloro-4-nitro-phenylsulfanyl)-5-trifluoromethyl-benzothiazole(258) (840 mg, 1.98 mmol) in EtOAc (20 mL) was added tin chloridedihydrate (Aldrich, 2.15 g, 9.52 mmol) and the resulting mixture washeated to reflux for 3 hours. After cooled to room temperature, to themixture was added excess of 4N aqueous NaOH solution and the resultingmixture was stirred for 20 minutes. The mixture was filtered throughCelite pad and washed with EtOAc. The organic layer was separated,washed twice with a brine solution, dried over Na₂SO₄, and concentratedunder vacuum to give compound 270 (755 mg, 96%) product as a pale yellowsolid, which was used in the next reaction without further purification.

[0881]¹H NMR (DMSO-d₆) δ 8.20-8.15 (m, 2H), 7.66 (dd, J=8.4,1.7 Hz, 1H),6.88 (s, 2H), 6.50 (s, 2H). MS (M+H) 395.

Example 271

[0882]1-[5-Amino-3-chloro-2-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone(271)

[0883] The title compound was prepared using the method of example 270,starting with1-[3-chloro-5-nitro-2-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone(259) (750 mg, 1,67 mmol), tin chloride dihydrate (Aldrich, 1.89 g, 8.37mmol). Compound 271 (755 mg, 100%) was obtained as a yellowish solid.

[0884]¹H NMR (DMSO-d₆) δ 8.20-8.13 (m, 2H), 7.66 (dd, J=8.4, 1.0 Hz,1H), 6.96 (d, J=2.4 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.43 (s, 2H), 2.48(s, 3H). MS (M+H) 403.

Example 272

[0885]2-(4-Amino-2,6-dichloro-phenylsulfanyl)-benzothiazole-6-carbonitrile(272)

[0886] The title compound was prepared using the method of example 270,starting with2-(2,6-dichloro-4-nitro-phenylsulfanyl)-benzothiazole-6-carbonitrile(260) (1.9 g, 4.97 mmol), tin chloride dihydrate (Aldrich, 5.62 g, 24.9mmol). Compound 272 (1.72 g, 98%) was obtained as a yellowish solid.

[0887]¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J=1.5 Hz,1H), 7.97 (d, J=8.7Hz, 1H), 7.86 (dd, J=8.5, 1.7 Hz, 1H), 6.88 (s, 2H), 6.53 (s, 2H). MS(M+H) 352.

Example 273

[0888] 2-(4-Amino-2-chloro-phenylsulfanyl)-benzothiazole-6-carbonitrile(273)

[0889] The title compound was prepared using the method of example 270,starting with2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazole-6-carbonitrile (261)(1.6 g, 4.6 mmol), tin chloride dihydrate (Aldrich, 5.21 g, 23.1 mmol).Compound 273 (1.36 g, 93%) was obtained as a yellowish solid. MS (M+H)318.

Example 274

[0890]2-(4-Amino-2,6-dichloro-phenylsulfanyl)-benzothiazole-5-carbonitrile(274)

[0891] The title compound was prepared using the method of example 270,starting with2-(2,6-dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carbonitrile(262) (1.9 g, 4.97 mmol), tin chloride dihydrate (Aldrich, 5.62 g, 24.9mmol). Compound 274 (1.40 g, 80%) was obtained as a yellowish solid.

[0892]¹H NMR (DMSO-d₆) δ 8.35 (d, J=1.4 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H),7.73 (dd, J=8.4, 1.5 Hz, 1H), 6.88 (s, 2H), 6.50 (s, 2H). MS (M+H) 352.

Example 275

[0893] 2-(4-Amino-2-chloro-phenylsulfanyl)-benzothiazole-5-carbonitrile(275)

[0894] The title compound was prepared using the method of example 270,starting with2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carbonitrile (263)(1.59 g, 4.58 mmol), tin chloride dihydrate (Aldrich, 5.18 g, 22.9mmol). Compound 275 (1.35 g, 93%) was obtained as a yellowish solid.

[0895]¹H NMR (DMSO-d₆) δ 8.32 (d, J=1.4 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H),7.71 (dd, J=8.3, 1.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 6.88 (d, J=2.4 Hz,1H), 6.65 (dd, J=8.4, 2.4 Hz, 1H). MS (M+H) 318.

Example 276

[0896]1-[5-Amino-3-chloro-2-(5-methyl-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone(276)

[0897] To a solution of1-[3-chloro-5-nitro-2-(5-methyl-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone(264) (3.87 g, 10.2 mmol) in 2:2:1 of EtOH/THF/H₂O, was added ammoniumchloride (Aldrich 2.74 g, 51.2 mmol) and iron powder (Aldrich, 2.87 g,51.2 mmol). The mixture was refluxed for 3 hours. The mixture wasfiltered through Celite pad while it was hot, washed the Celite pad withEtOAc. The filtrate was diluted with saturated aqueous NaHCO₃ solutionand was extracted 3× with EtOAc (150 mL). The organic layers werecombined and washed twice with a brine solution (100 mL), dried overNa₂SO₄, and concentrated under vacuum. The crude solid waschromatographed (0-15% EtOAc in CH₂Cl₂) to yield 2.42 g (68%) ofcompound 276 as a pale yellow solid.

[0898]¹H NMR (DMSO-d₆) δ 8.10 (d, J=8.1 Hz, 1H), 7.62 (d, J=1.1 Hz, 1H),7.16 (dd, J=8.1, 1.2 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.69 (d, J=2.5 Hz,1H), 6.38 (s, 2H), 2.46 (s, 3H), 2.40 (s, 3H). MS (M+H) 349.

[0899] Examples 277-307: The compounds illustrated in Table 32 wereprepared by sulfonylation of the anilines of Table 31 by the method ofExample 277 unless otherwise specified. TABLE 32

Example # C D V W X Y MS(M − H) Yield 277 CF₃ H COMe Cl H Cl 609 72% 278Cl H COMe Cl H Cl 575 39% 279 Cl Me COMe Cl H Cl 589 73% 280 Cl H H Cl HCF₃ 567 68% 281 CF₃ H H Cl H CF₃ 601 70% 282 Cl H H Cl H CO₂Me 557 68%283 Cl H Cl Cl H CO₂Me 557 68% 284 CF₃ H H Cl CONH₂ H 576 14% 285 CF₃ HCl Cl CONH₂ H 610 55% 286 CF₃ H H Cl CN₄H H 601 67% 287 CF₃ H Cl Cl CN₄HH 635 65% 288 CF₃ H H OMe H Cl 563 72% 289 Cl H Cl Cl H CF₃ 601 61% 290CF₃ H Cl Cl H CF₃ 635 76% 291 Cl H COMe Cl H CF₃ 609 32% 292 CF₃ H COMeCl H CF₃ 643 29% 293 Cl H Cl Cl CN H 558 71% 294 CF₃ H Cl Cl CN H 59283% 295 Cl H H Cl CN H 524 88% 296 CF₃ H H Cl CN H 558 64% 297 Cl H ClCl H CN 558 66% 298 CF₃ H Cl Cl H CN 592 72% 299 Cl H H Cl H CN 524 58%300 CF₃ H H Cl H CN 558 58% 301 Cl H Cl Cl H CN₄H 601 77% 302 CF₃ H ClCl H CN₄H 635 82% 303 Cl H Cl Cl H CONH₂ 601 77% 304 Cl H H Cl H CN₄H567 78% 305 CF₃ H H Cl H CN₄H 601 83% 306 CF₃ H COMe Cl H Me 589 73% 307Cl Me COMe Cl H Me 569 74%

Example 277

[0900] N-[3-Acetyl-5-chloro4-(5-chloro-benzothiazol-2-ylsulfanyl)-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide (277)

[0901] To a 1M solution of1-[5-Amino-3-chloro-2-(5-chloro-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone,(265) (4.12 g, 11.19 mmol) in pyridine, obtained from Aldrich, was added2-chloro-4-trifluoromethyl-benzenesulfonyl chloride (3.75 g, 13.43 mmol)and heated to 90° C. for 1.5 hours. The crude reaction mixture wasconcentrated under vacuum, partitioned between 2M aqueous HCl (100 mL)and EtOAc (100 mL), and extracted 3 times with EtOAc (100 mL). Thecombined organic layers were washed twice with saturated aqueous brine(100 mL), dried over Na₂SO₄, concentrated under vacuum, purified bycolumn chromatography (0-5% Et₂O in CH₂Cl₂), and triturated withCH₂Cl₂/hexane mixture with 0.5 mL of MeOH added to yield compound 277(4.9 g, 72%) as an off white solid.

[0902]¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (s, 1H), 8.43 (d, J=8.2 Hz, 1H),8.23 (s, 1H), 8.01 (bd, J=7.2 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.9 (d,J=2.1 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.42 (dd, J=8.6, 2.1 Hz, 1H),7.31 (d, J=2.4 Hz, 1H), 2.45 (s, 3H). MS (EI): m/z 609 (38, M−H), 610(10, M−H), 611 (50, M−H), 612 (12, M−H), 613 (20, M−H), 614 (5, M−H),615 (3, M−H).

Example 278

[0903]N-[3-Acety-5-chloro4-(5-chloro-benzothiazol-2-ylsulfanyl)-phenyl]-2,4-dichloro-benzenesulfonamide(278) By the method of example 93. ¹H NMR (DMSO-d₆) δ 11.8 (s, 1H), 8.24(d, J=8.6 Hz, 1H), 8.1-7.95 (m, 2 H), 7.91 (d, J=2.0 Hz, 1H), 7.71 (dd,J=8.6, 2.1 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.42 (dd, J=8.6, 2.1 Hz,1H), 7.29 (d, J=2.4 Hz, 1H), 2.45 (s, 3H). MS (M−H) 575.

Example 279

[0904]N-[3-Acetyl-5-chloro4-(5-chloro-benzothiazol-2-ylsulfanyl)-phenyl]-2,4-dichloro-5-methyl-benzenesulfonamide(279)

[0905]¹H NMR (DMSO-d₆) δ 11.8 (s, 1H), 8.3 (s, 1H), 7.98 (d, J=8.6 Hz,1H), 7.93-7.9 (m, 2H), 7.46 (d, J=2.4 Hz, 1H), 7.42 (dd, J=8.6, 2.1 Hz,1H), 7.3 (d, J=2.4 Hz, 1H), 2.45 (s, 3H), 2.4 (s, 3H). MS (M−H) 589.

Example 280

[0906]2,4-Dichloro-N-[3-chloro4-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide(280)

[0907]¹H NMR (400 MHz, DMSO-d₆) δ 11.6 (s, 1 H), 8.23-8.16 (m, 3 H),7.96 (bs, 1 H), 7.88 (bd, J=8.6 Hz, 1H), 7.75-7.67 (m, 2 H), 7.4 (bs,1H), 7.23 (bd, J=10.7 Hz, 1 H). MS M−H) 567.

Example 281

[0908]2-Chloro-N-[3-chloro-4-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenyl]4-trifluoromethyl-benzenesulfonamide(281)

[0909]¹H NMR (400 MHz, DMSO-d₆) δ 11.8 (s, 1 H), 8.4 (d, J=8.3 Hz, 1 H),8.23 (bs, 1 H), 7.98-7.94 (m, 2 H), 8.03 (bd, J=8.4 Hz, 1 H), 7.9 (d,J=8.6 Hz, 1H), 7.69 (bd, J=10.1 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.25(dd, J=8.5, 2.4 Hz, 1 H). MS (M−H) 601.

Example 282

[0910]2-[2-Chloro4-(2,4-dichloro-benzenesulfonylamino)-phenylsulfanyl]-benzothiazole-5-carboxylicacid methyl ester(282)

[0911]¹H NMR (DMSO-d₆) δ11.5 (s, 1H), 8.32 (d, J=1.5 Hz, 1H), 8.19 (d,J=8.6 Hz, 1H), 8.08 (d,=8.4 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.92 (dd,J=9.1, 1.6 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.73 (dd, J=8.6, 2.1 Hz,1H), 7.4 (d, J=2.2 Hz, 1H), 7.22 (dd, J=8.2, 2.0 Hz, 1 H), 3.9 (s, 3H).MS (M−H) 557.

Example 283

[0912]2-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenylsulfanyl]-benzothiazole-5-carboxylicacid methyl ester(283) By the method of example 93.

[0913]¹H NMR (DMSO-d₆) δ 11.9 (s, 1H), 8.32 (d, J=0.9 Hz, 1H), 8.22 (d,J=8.6 Hz, 1 H), 8.09 (d, =8.4 Hz, 1H), 8.0 (d, J=1.9 Hz, 1H), 7.92 (dd,J=8.4, 1.6 Hz, 1 H), 7.75 (dd, J=8.6, 2.1 Hz, 1H), 7.4 (s, 2H), 3.9 (s,3H). MS (M−H) 591.

Example 284

[0914]2-[2-Chloro4-(2-chloro-4-trifluoromethyl-benzenesulfonylamino)-phenylsulfanyl]-benzothiazole-6-carboxylicacid amide (284)

[0915]2-[2-Chloro-4-(2-chloro-4-trifluoromethyl-benzenesulfonylamino)-phenylsulfanyl]-benzothiazole-6-carboxylicacid amide (284) was prepared (14%) from2-chloro-N-[3-chloro-4-(6-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(296) by the method of example 303.

[0916]¹H NMR (DMSO-d₆) δ 11.8 (s, 1H), 8.42 (d, J=1.3 Hz, 1H), 8.38 (d,J=8.5 Hz, 1 H), 8.21 (bs, 1H), 8.05-7.99 (m, 2H), 7.94 (dd, J=8.6, 1.5Hz, 1 H), 7.89-7.83 (m, 2H), 7.45 (s, 1H), 7.42 (d, J=1.9 Hz, 1H), 7.24(dd, J=8.5, 2.1 Hz, 1H). MS (M−H) 576.

Example 285

[0917]2-[2,6-Dichloro-4-(2-chloro-4-trifluoromethyl-benzensulfonylamino)-phenylsulfanyl]-benzothiazole-6-carboxylicacid amide (285)

[0918]2-[2,6-Dichloro-4-(2-chloro-4-trifluoromethyl-benzensulfonylamino)-phenylsulfanyl]-benzothiazole-6-carboxylicacid amide (285) was prepared (55%) from2-chloro-N-[3,5-dichloro-4-(6-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(294), by the method of example 303.

[0919]¹H NMR (DMSO-d₆) δ 12.0 (bs, 1H), 8.48-8.4 (m, 2H), 8.23 (bs, 1H),8.05-8.0 (m, 2H), 7.95 (dd, J=8.5, 1.7 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H),7.48 (s, 1H), 7.4 (s, 2H). MS (M−H) 610.

Example 286

[0920]2-Chloro-N-{3-chloro-4-[6-(1H-tetrazol-5-yl)-benzothiazol-2-ylsulfanyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide

[0921]2-Chloro-N-{3-chloro-4-[6-(1H-tetrazol-5-yl)-benzothiazol-2-ylsulfanyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide(286) was prepared (67%) from2-chloro-N-[3-chloro-4-(6-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(296) ), by the method of example 301.

[0922]¹H NMR (DMSO-d₆) δ 8.62 (bs, 1H), 8.36 (d, J=8.5 Hz, 1H), 8.19(bs, 1H), 8.08 (d, J=8.1 Hz, 1H), 8.04-7.95 (m, 2H), 7.84 (d, J=8.6 Hz,1H), 7.38 (d, J=2.0 Hz, 1H), 7.2 (dd, J=7.9, 1.8 Hz, 1H). MS (M−H) 601.

Example 287

[0923]2-Chloro-N-{3,5-dichloro4-[6-(1H-tetrazol-5-yl)-benzothiazol-2-ylsulfanyl]-phenyl}4-trifluoromethyl-benzenesulfonamide(287)

[0924]2-Chloro-N-{3,5-dichloro-4-[6-(1H-tetrazol-5-yl)-benzothiazol-2-ylsulfanyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide(287) was prepared (65%) from2-chloro-N-[3,5-dichloro-4-(6-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(294) by the method of example 301.

[0925]¹H NMR (DMSO-d₆) δ 8.65 (bs, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.24(bs, 1H), 8.09 (d, J=8.6 Hz, 1 H), 8.06-7.98 (m, 2H), 7.4 (bs, 2H). MS(M−H) 635.

Example 288

[0926]2-Chloro-N-[4-(5-chloro-benzothiazol-2-ylsulfanyl)-3-methoxy-phenyl]-4-trifluoromethyl-benzenesulfonamide(288) By the method of example 93.

[0927]¹H NMR (DMSO-d₆) δ 11.5 (s, 1H), 8.4 (d, J=8.3 Hz, 1H), 8.2 (bs,1H), 8.01 (d, J=8.3, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.87 (d, J=2.1 Hz,1H), 7.63 (d, J=8.4 Hz, 1H), 7.38 (dd, J=8.6, 2.0 Hz, 1H), 6.96 (d,J=2.0 Hz, 1H), 6.83 (dd, J=8.4, 2.1 Hz, 1H), 3.8 (s, 3H). MS (M−H) 563.

Example 289

[0928]2,4-Dichloro-N-[3,5-dichloro4-(5-trifuoromethyl-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide(289)

[0929]¹H NMR (DMSO-d₆) δ 11.90 (s, 1H), 8.25-8.15 (m, 3H), 7.98 (d,J=2.0 Hz, 1H), 7.76-7.67 (m, 2H), 7.38 (s, 2H). MS (M−H) 601.

Example 290

[0930]2-Chloro-N-[3,5-dichloro4-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenyl]4-trifluoromethyl-benzenesulfonamide(290)

[0931]¹H NMR (DMSO-d₆) δ 11.90 (br s, 1H), 8.43 (d, J=8.4 Hz, 1H),8.26-8.15 (m, 3H), 8.03 (dd, J=8.4, 1.7 Hz, 1H), 7.68 (dd, J=8.6, 1.6Hz, 1H), 7.40 (s, 2H). MS (M−H) 635.

Example 291

[0932]N-[3-Acetyl-5-chloro-4-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenyl]-2,4-dichloro-benzenesulfonamide(291)

[0933]¹H NMR (DMSO-d₆) δ 11.80 (br s, 1H), 8.25 (d, J=8.6 Hz, 1H),8.22-8.15 (m, 2H), 7.97 (d, J=2.1 Hz, 1H), 7.72 (dd, J=8.6, 2.1 Hz, 1H),7.69 (dd, J=8.6, 1.6 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.31 (d, J=2.4 Hz,1H), 2.47 (s, 3H). MS (M−H) 609.

Example 292

[0934]N-[3-Acetyl-5-chloro-4-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenyl]-2-chloro4-trifluoromethyl-benzenesulfonamide(292)

[0935]¹H NMR (DMSO-d₆) δ 11.90 (br s, 1H), 8.42 (d, J=8.1 Hz, 1H),8.23-8.17 (m, 3H), 8.01 (dd, J=8.5, 1.4 Hz, 1H), 7.65 (dd, J=8.5, 1.5Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 2.48 (s, 3H).MS (M−H) 643.

Example 293

[0936]2,4-Dichloro-N-[3,5-dichloro4-(6-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide(293)

[0937]¹H NMR (DMSO-d₆) δ 11.90 (br s, 1H), 8.49 (d, J=1.1 Hz, 1H), 8.23(d, J=8.6 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.86(dd, J=8.5, 1.6 Hz, 1H), 7.74 (dd, J=8.6, 2.0 Hz, 1H), 7.38 (s, 2H). MS(M−H) 558.

Example 294

[0938]2-Chloro-N-[3,5-dichloro-4-(6-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(294)

[0939]¹H NMR (DMSO-d₆) δ 11.90 (br s, 1H), 8.49 (d, J=1.5 Hz, 1H), 8.43(d, J=8.1 Hz, 1H), 8.24 (br s, 1H), 8.03 (dd, J=8.2, 1.0 Hz, 1H), 7.97(d, J=8.5 Hz, 1H), 7.87 (dd, J=8.5, 1.7 Hz, 1H), 7.40 (s, 2H). MS (M−H)592.

Example 295

[0940]2,4-Dichloro-N-[3-chloro4-(6-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide(295)

[0941]¹H NMR (DMSO-d₆) δ 11.60 (br s, 1H), 8.49 (d, J=1.8 Hz, 1H), 8.18(d, J=8.6 Hz, 1H), 8.00-7.94 (m, 2H), 7.90-7.84 (m, 2H), 7.72 (dd,J=8.6, 2.0 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.23 (dd, J=8.5, 2.4 Hz,1H). MS (M−H) 524.

Example 296

[0942]2-Chloro-N-[3-chloro4-(6-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(296)

[0943]¹H NMR (DMSO-d₆) δ 11.78 (br s, 1H), 8.48 (br s, 1H), 8.39 (d,J=8.0 Hz, 1H), 8.22 (br s, 1H), 8.02 (br d, J=8.4 Hz, 1H), 7.97 (d,J=8.6 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.86 (dd, J=8.5, 1.5 Hz, 1H),7.43 (d, J=2.3 Hz, 1H), 7.25 (dd, J=8.5, 2.4 Hz, 1H). MS (M−H) 558.

Example 297

[0944]2,4-Dichloro-N-[3,5-dichloro4-(5-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide(297)

[0945]¹H NMR (DMSO-d₆) δ 11.90 (br s, 1H), 8.36 (d, J=1.1 Hz, 1H), 8.23(d, J=8.5 Hz, 1H), 8.16 (d, J=8.2 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.77(dd, J=8.5, 1.5 Hz, 1H), 7.73 (dd, J=8.4, 2.0 Hz, 1H), 7.38 (s, 2H). MS(M−H) 558.

Example 298

[0946]2-Chloro-N-[3,5-dichloro-4-(5-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(298)

[0947]¹H NMR (DMSO-d₆) δ 11.98 (br s, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.35(d, J=1.5 Hz, 1H), 8.23 (br s, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.03 (dd,J=8.4, 1.0 Hz, 1H), 7.76 (dd, J=8.4, 1.4 Hz, 1H), 7.40 (s, 2H). MS (M−H)592.

Example 299

[0948]2,4-Dichloro-N-[3-chloro-4-(5-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide

[0949]¹H NMR (DMSO-d₆) δ 11.60 (br s, 1H), 8.36 (d, J=1.5 Hz, 1H), 8.18(d, J=8.6 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.88(d, J=8.6 Hz, 1H), 7.75 (dd, J=8.4, 1.5 Hz, 1H), 7.72 (dd, J=8.5, 2.0Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.23 (dd, J=8.5, 2.4 Hz, 1H). MS (M−H)524.

Example 300

[0950]2-Chloro-N-[3-chloro4-(5-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(300)

[0951]¹H NMR (DMSO-d₆) δ 11.70 (br s, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.35(d, J=1.4 Hz, 1H), 8.21 (br s, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.03 (dd,J=8.5, 1.5 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.75 (dd, J=8.4, 1.6 Hz,1H), 7.43 (d, J=2.4 Hz, 1H), 7.24 (dd, J=8.5, 2.4 Hz, 1H). MS (M−H) 558.

Example 301

[0952]2,4-Dichloro-N-{3,5-dichloro-4-[5-(1H-tetrazol-5-yl)-benzothiazol-2-ylsulfanyl]-phenyl}-benzenesulfonamide(301)

[0953] To a solution of2,4-dichloro-N-[3,5-dichloro-4-(5-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide(297) (250 mg, 0.45 mmol) in toluene (5 mL), was addedazidotrimethylsilane (Aldrich, 0.12 mL, 0.90 mmol) and dibutyltin oxide(Aldrich, 11 mg, 0.045 mmol). The resulting mixture was heated at 90° C.overnight (15 hours). A 1 M aqueous solution of HCl (50 mL) and ice wasadded and the crude reaction mixture was extracted 3× with EtOAc (50mL). The organic layers were combined and washed twice with a brinesolution (100 mL), dried over Na₂SO₄, and concentrated under vacuum. Thecrude solid was chromatographed (20% EtOAc in CH₂Cl₂, then 10% MeOH inCH₂Cl₂) to yield 209 mg (77%) of product as a white solid.

[0954]¹H NMR (DMSO-d₆) δ 8.44 (d, J=1.7 Hz, 1H), 8.21 (d, J=8.6 Hz, 1H),8.16 (d, J=8.4 Hz, 1H), 8.01 (dd, J=8.4, 1.7 Hz, 1H), 7.96 (d, J=2.0 Hz,1H), 7.72 (dd, J=8.6, 2.0 Hz, 1H), 7.38 (s, 2H). MS (M−H) 601.

Example 302

[0955]2-Chloro-N-{3,5-dichloro4-[5-(1H-tetrazol-5-yl)-benzothiazol-2-ylsulfanyl]-phenyl}4-trifluoromethyl-benzenesulfonamide(302)

[0956] The title compound was prepared by the method of example 301.

[0957]¹H NMR (DMSO-d₆) δ 8.44 (d, J=1.5 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H),8.23 (d, J=1.3 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.02 (dd, J=8.4, 1.4 Hz,1H), 7.40 (s, 2H). MS (M−H) 635.

Example 303

[0958]2-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenylsulfanyl]-benzothiazole-5-carboxylicacid amide (303)

[0959] To a solution of2,4-dichloro-N-[3,5-dichloro-4-(5-cyano-benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide(297) (250 mg, 0.45 mmol) in tert-butanol (10 mL), was added KOH (EMScience Product, 126 mg, 2.25 mmol). The resulting mixture was refluxedfor 1 hour. After cooling to room temperature, a 1M aqueous solution ofHCl (50 mL) was added and the crude reaction mixture was extracted 3×with EtOAc (50 mL). The organic layers were combined and washed twicewith a brine solution (100 mL), dried over Na₂SO₄, and concentratedunder vacuum. The crude solid was chromatographed (20% EtOAc in CH₂Cl₂,then 10% MeOH in CH₂Cl₂) to yield 207 mg (80%) of compound 303 as awhite solid.

[0960]¹H NMR (DMSO-d₆) δ 11.80 (s, 1H), 8.33 (br s, 1H), 8.22 (dd,J=8.5, 1.9 Hz, 1H), 8.08 (br s, 1H), 8.03-7.96 (m, 2H), 7.85 (m, 1H),7.74 (m, 1H), 7.47 (br s, 1H), 7.38 (s, 2H). MS (M−H) 578.

Example 304

[0961]2,4-Dichloro-N-{3-chloro-4-[5-(1H-tetrazol-5-yl)-benzothiazol-2-ylsulfanyl]-phenyl}-benzenesulfonamide(304) The title compound was prepared by the method of example 301.

[0962]¹H NMR (DMSO-d₆) δ 8.44 (d, J=1.5 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H),8.14 (d, J=8.4 Hz, 1H), 8.01 (dd, J=8.4, 1.6 Hz, 1H), 7.95 (d, J=2.1 Hz,1H), 7.87 (d, J=8.6 Hz, 1H), 7.71 (dd, J=8.6, 2.1 Hz, 1H), 7.39 (d,J=2.4 Hz, 1H), 7.21 (dd, J=2.4 Hz, 1H). MS (M−H) 567.

Example 305

[0963]2-Chloro-N-{3-chloro4-[5-(1H-tetrazol-5-yl)-benzothiazol-2-ylsulfanyl]-phenyl}4-trifluoromethyl-benzenesulfonamide(305).

[0964] The title compound was prepared by the method of example 301.

[0965]¹H NMR (DMSO-d₆) δ 8.43 (d, J=1.5 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H),8.17 (d, J=1.4 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 8.03-7.96 (m, 2H), 7.85(d, J=8.6 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.20 (dd, J=8.6, 2.4 Hz, 1H).MS (M−H) 601.

Example 306

[0966]N-[3-Acetyl-5-chloro4-(5-methyl-benzothiazol-2-ylsulfanyl)-phenyl]-2-chloro4-trifluoromethyl-benzenesulfonamide(306).

[0967] 1H NMR (DMSO-d₆) δ 11.90 (br s, 1H), 8.43 (d, J=8.1 Hz, 1H), 8.23(d, J=1.2 Hz, 1H), 8.01 (dd, J=8.4, 1.1 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H),7.62 (s, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.19 (dd,J=8.5, 1.2 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H). MS (M−H) 5.89.

Example 307

[0968]N-[3-Acetyl-5-chloro4-(5-methyl-benzothiazol-2-ylsulfanyl)-phenyl]-2,4-dichloro-5-methyl-benzenesulfonamide(307)

[0969]¹H NMR (DMSO-d₆) δ 11.70 (br s, 1H), 8.28 (s, 1H), 7.92 (s, 1H),7.80 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.29 (d,J=2.3 Hz, 1H), 7.19 (dd, J=8.2, 1.5 Hz, 1H), 2.48-2.38 (m, 9H). MS (M−H)569.

Example 308

[0970] 3-Hydroxy-6-methylquinoline (308)

[0971] A solution of 3-Amino-6-methylquinoline [(1.21 g, 7.65 mmol),prepared according to J. Chem. Soc. 2024-2027 (1948) Morley, J. S.;Simpson, J. C. E.] in 6N H₂SO₄ (25 ml) was cooled in an ice bath. To thesolution NaNO₂ (560 mg, 8.10 mmol) in water (2 ml) was added and stirredfor 30 min at 0 degrees. Separately 5% H₂SO₄ was refluxed and aboveDiazo reaction mixture was added to this refluxing solution. After 30min the reaction mixture was cooled to room temperature, and wasneutralized by 6N NaOH. The resulting insoluble material was collectedby filtration. This solid was recrystallized by CHCl₃/AcOEt to affordcompound (308) (348 mg, 29%).

[0972]¹H NMR (300 MHz,DMSO-d₆) δ 7.34 (1H, dd, J=1.9, 8.6 Hz), 7.42(1H,d, J=2.8 Hz), 7.55 (1H, s), 7.79 (1H, d, J=8.6 Hz), 8.50 (1H, d, J=2.8Hz).

Example 309

[0973] 3-(2,6-Dichloro4-nitro-phenoxy)-6methyl-quinoline (309)

[0974] To a solution of 3-Hydroxy-6-methylquinoline (308) (348 mg, 2.19mmol) in DMF (3.5 ml), was added NaH (60% oil suspension, 90 mg, 2.25mmol) in one portion at room temperature. After 5 min3,4,5-Trichloronitorobenzene (509 mg, 2.25 mmol) in DMF (2 ml) was addedand the reaction mixture was heated at 50 degrees with stirring for 2hr. After cooling to room temperature. Ice/water was added to thereaction mixture, which was then acidified with 2N HCl and extractedtwice with AcOEt. Organic layer was washed with Brine, dried overanhydrous MgSO₄, and concentrated. Crude residue was purified by columnchromatography (Hexane/AcOEt=4/1, 80 g of silica gel) to afford compound309 (510 mg, 67%).

[0975]¹H NMR (300 MHz, DMSO-d₆) δ 7.52-7.57 (2H,m), 7.61 (1H, s), 7.94(1H, d, J=8.6 Hz), 8.63 (2H, s), 8.86 (1H, d, J=2.9 Hz).

Example 310

[0976] 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid(310).

[0977] A solution of3-(2,6-Dichloro-4-nitro-phnoxy)-6-methyl-quinoline(309) (510 mg, 1.46mmol) and chromium (VI) oxide (292 mg, 2.92 mmol) in c H₂SO₄/H₂O=2.4ml/4.7 ml was heated at 100 degrees while three 292 mg portions ofchromic anhydride were added eight hour intervals. After 32 hr heatingwas stopped and allowed to stand for over night. Insoluble material wascollected by filtration, and this solid was washed with water twice toafford compound (310)(443 mg, 80%).

[0978]¹H NMR (300 MHz, DMSO-d₆) δ 7.94 (1H, d, J=3.0 Hz), 8.14(2H, s),8.56 (1H, s), 8.65 (2H, s), 9.09 (1H, d, J=3.0 Hz).

Example 311

[0979] 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acidmethyl ester (311)

[0980] To a solution of3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid (310) (443mg, 0.93 mmol) in dry THF (20 ml) was added CH₂N₂ in Et₂O solution[Prepared from Nitrosomethylurea (1.65 g) and 50% KOH (5 ml)]. Thismixture was stirred at room temperature for 1 hr. AcOH (1 ml) was addedto the reaction mixture, which was then concentrated. Sat NaHCO₃ wasadded to the residue, which was extracted twice with AcOEt. Organiclayer was washed by Brine, dried over anhydrous MgSO₄, and concentratedto afford compound 311 (415 mg).

[0981]¹H NMR (300 MHz, DMSO-d₆) δ 3.89 (3H, s), 5.75 (2H, br s), 6.76(2H, s), 7.73 (1H, d, J=2.9 Hz), 8.09 (2H, s), 8.67 (1H, s), 8.94 (1H,d, J=2.9 Hz).

Example 312

[0982] 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-6-carboxylic acidmethyl ester (312)

[0983] To a solution of3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid methylester (311) (0.93 mmol) and NH4Cl (283 mg, 5.3 mmol) in EtOH/THF/water(8 ml/16 ml/1 ml )was added Iron powder (296 mg, 5.3 mmol). The reactionmixture was refluxed for 4 hr. Insoluble materials were removed byCelite pad, which was washed by THF, acetone and then EtOH. The filtratewas concentrated, and sat NaHCO₃ was added and extracted twice withAcOEt. Organic layer was washed by brine, dried over anhydrous MgSO₄,and concentrated to afford compound 312 (372 mg, over weight).

[0984]¹H NMR (300 MHz, DMSO-d₆) δ 3.89 (3H, s), 5.75 (2H,s), 6.76 (2H,s), 7.73 (1H, d, J=2.9 Hz), 8.09 (2H, s), 8.67 (1H, s), 8.94 (1H, d,J=2.9 Hz).

Example 313

[0985] 3-Hydroxy-8-quinolinecarboxylic acid methyl ester (313)

[0986] To the mixture of 8-Quinoline carboxylic acid (500 mg, 2.89 mmol)in THF (80 ml) was added CH₂N₂ in Et₂O sol. [Prepared fromNitrosomethylurea (1.65 g) and 50% KOH (5 ml)] at room temperature. Thereaction mixture was stirred for 12 hr and then concentrated to give theintermediate ester.

[0987]¹H NMR (300 MHz, DMSO-d₆) δ 3.92 (3H, s), 7.60-7.70 (2H, m),7.93-7.96 (1H, m), 8.14-8.17 (1H, m), 8.44-8.48 (1H, m), 8.97-8.99 (1H,m).

[0988] To a solution of the intermediate 8-Quinolinecarboxylic acidmethyl ester (2.89 mmol) in AcOH (4 ml) was added 30% H₂O₂ (0.6 ml). Thereaction mixture was heated at 85 degrees for 7.5 hr. The reactionmixture was treated with sat NaHCO₃, and extracted six times with CHCl₃.Organic layer was dried over anhydrous MgSO₄, and concentrated. Cruderesidue was triturated with CHCl₃/Toluene to provide compound 313 (256mg, 44%, in 2 steps).

[0989]¹H NMR (300 MHz, DMSO-d₆) δ 3.89 (3H, s), 7.52 (1H, d, J=6.9 Hz),7.57 (1H, d, J=1.5 Hz), 7.66 (1H, dd, J=1.5, 6.9 Hz), 7.95 (1H, dd,J=1.5, 8.1 Hz), 8.63 (1H, d, J=2.7 Hz), 10.5 (1H, br s).

Example 314

[0990] 3-(2,6-Dichloro4-nitro-phenoxy)-quinoline-8-carboxylic acidmethyl ester (314)

[0991] To a solution of 3-Hydroxy-8-quinolinecarboxylic acid methylester (313) (256 mg, 1.26 mmol) and 3,4,5-Trichloronitrobenzene (294 mg,1.30 mmol) in Acetone (40 ml) was added K₂CO₃ (870 mg, 6.30 mmol). Thismixture was refluxed for 3.5 hr. The reaction mixture was cooled to roomtemperature and insoluble materials were removed by Celite filtration.The filtrate was concentrated and the residue was purified by columnchromatography. (Hexane/AcOEt=4/1, 80 g of silica gel) to affordcompound 314.

[0992]¹H NMR (300 MHz, DMSO-d₆) δ 3.92 (3H, s), 7.67 (1H, dd, J=7.3 Hz),7.79 (1H, d, J=2.9 Hz), 7.88 (1H, dd, J=1.5, 7.3 Hz), 9.05 (1H, d, J=2.9Hz).

Example 315

[0993] 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-8-carboxylic acidmethyl ester(315).

[0994] To a solution of3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-8-carboxylic acid methylester (314) (1.26 mmol) and NH₄Cl (370 mg, 6.91 mmol) in EtOH/THF/H₂O=8ml/4 ml/2 ml was added Iron powder (386 mg, 6.91 mmol). The reactionmixture was.refluxed for 3.5 hr. After cooling to room temperature andinsoluble materials were filtered by Celite filtration. The filtrate wasconcentrated and sat NaHCO₃ was added to the residue, which wasextracted twice with AcOEt. Organic layer was washed by Brine, driedover MgSO₄, and concentrated. Crude residue was purified by columnchromatography (Hexane/AcOEt=2/1, 80 g of silica gel) to afford compound315 (543 mg).

[0995]¹H NMR (300 MHz, DMSO-d₆) δ 3.91 (3H, s), 5.77 (2H, br s), 6.78(2H, s), 7.50 (1H, d, J=3.0 Hz), 7.61 (1H, dd, J=8.1 Hz), 7.81 (1H, dd,J=1.4, 6.4 Hz), 8.08 (1H, dd, J=1.4 Hz, 6.4 Hz), 8.93 (1H, d, J=3.0 Hz).TABLE 33

Example # V X Y Z 316 H Cl H Cl 317 H F F H 318 H F H F 319 Cl Me Me H

Example 316

[0996] 3-chloro-4-(3,5-dichloro-phenylsulfanyl)-phenylamine (316).

[0997] A solution of potassium t-butoxide (1M in THF) (13 ml) was addedvia syringe to a solution of 3,5 dichlorothiophenol (2.37 g) and3-chloro-4-fluoro-nitrobenzene (2.3 g) in THF (20 mL). The exothermicreaction was allowed to stir until it cooled to room temperature. It waspoured into water. The resulting solid was collected by filtration andrinsed quickly with ether to leave the intermediate nitro compound. (3.5g). This was dissolved in ethyl acetate at reflux. Tin (II) chloridedihydrate (2.3 g) was added in portions as a solid and the refluxcontinued for 2 hr. After cooling, the mixture was diluted in ethylacetate, quenched with KOH (0.5 N, 500 mL) and extracted with ethylacetate 3×. The organic layer was washed with water, dried overmagnesium sulfate and concentrated to afford the aniline (316) (2.9 g)as a light tan solid useable in subsequent reactions. Mp 157-160° C.

[0998]¹H NMR (DMSO) δ 7.36 (d, J=8.4 Hz, 1H), 7.341 (t, J=2 Hz, 1H),6.91 (m, 2H), 6.831 (d, J=2.4 Hz, 1H), 6.602 (dd, J=8.4, 2.8 Hz, 1H),6.01 (br s, 2H).

Examples 317 AND 318

[0999] 3,4 difluorothiophenol and 3,5-difluorothiophenol were preparedby the method of D. K. Kim et al (J. Med. Chem. 40, 2363-2373 (1997) andconverted by the method of example 316 to the corresponding anilines.

Example 317

[1000] 3-chloro-4-(3,5-difluoro-phenylsulfanyl)-phenylamine (317)

[1001]¹H NMR (DMSO) δ 7.361 (d, J=8.4 Hz, 1H), 6.983 (m, 1H), 6.84 (d,J=2.4 Hz, 1H) 6.61 (m, 3H), 6.02 (s, 2H).

Example 318

[1002] 3-chloro-4-(3,4-difluoro-phenylsulfanyl)-phenylamine (318)

[1003]¹H NMR (acetone) δ 7.377 (d, J=8.4 Hz, 1H), 7.258 (dt J=10.4, 8.4Hz, 1H), 6.97 (m, 1H) 6.94 (m, 2H), 6.714 (dd, 8.4, 2.5 Hz, 1H), 5.42(s, 2H).

Example 319

[1004] 3,5-Dichloro-4-(3,4-dimethyl-phenylsulfanyl)-phenylamine (319).

[1005] A mixture of 3,4-dimethylthiophenol (1.38 g, 10 mmol),3,4,5-trichoronitrobenzene 2.49 g, 11 mmol) and K₂CO₃ (4.15 g, 30 mmol)in acetone (15 ml) was refluxed for 2 hr. After reaction mixture wasconcentrated, crude product was purified by column chromatography(H/A=9/1, 180 g of silica gel) to afford a yellow oil. Unpurified crude3,5-Dichloro-4-(3,4-dimethyl-phenylsulfanyl)-nitrobenzene was dissolvedin CH₂Cl₂/AcOEt (5 ml/20 ml). To the solution was added SnCl₂/2H₂O (9.03g, 40 mmol) and the reaction mixture was stirred at room temperature for12 hr. 30% NaOH was added to the reaction mixture, which was extractedtwice with AcOEt. Organic layer was washed by water, dried over MgSO₄and concentrated to give 2.86 g (96% 2 steps) of compound 319 as a whitesolid.

[1006]¹H NMR (300 MHz, DMSO-d₆) δ 2.14 (6H, s), 6.11 (2H, br s), 6.66(1H, dd, J=1.8, 8.1 Hz), 6.77(2H, s), 6.82 (1H, d, J=1.8 Hz), 7.02 (1H,d, J=8.1 Hz). TABLE 34

EXAMPLE MS # k A B C D V X V Z (M − H) 320 O Cl H Cl H H Cl H Cl 509.9321 1 Cl H Cl H H Cl H Cl 525.8 322 2 Cl H Cl H H Cl H Cl 541.8 323 O ClH Cl H H F H F 478 324 1 Cl H Cl H H F H F 325 2 Cl H Cl H H F H F 509.9326 0 Cl H CF₃ H H F H F 512 327 1 Cl H CF₃ H H F H F 461 328 2 Cl H CF₃H H F H F 544 329 0 Cl H Cl Me H F H F 491.9 330 1 Cl H Cl Me H F H F331 2 Cl H Cl Me H F H F 523.8 332 O Cl H Cl H H F F H 333 1 Cl H Cl H HF F H 493.9 334 2 Cl H Cl H H F F H 509.9 335 O Cl H CF₃ H H F F H 512336 1 Cl H CF₃ H H F F H 493.9 337 2 Cl H CF₃ H H F F H 544 338 0 Cl HCF₃ H Cl Me Me H 540

Examples 320-337

[1007] The anilines of Table 33 were sulfonylated by the method ofexample 3 and then oxidized to the corresponding sulfoxide by the methodof example 103 or sulfone by the method of example 104 to provide theexamples 320-337 illustrated in Table 34.

Example 324

[1008]¹H NMR (DMSO) δ 11.5 (br s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.88 (d,J=2 Hz, 1H), 7.748 (d, J=8 Hz, 1H), 7.661 (dd, J=8.8, 2 Hz, 1H), 7.476(m, 1H), 7.42 (m, 2H), 7.28 (dd, J=8.4, 2 Hz, 1H) 7.17 (br s, 1H).

Example 330

[1009]¹H NMR (acetone) δ 10.1 (br s, 1H), 8.147 (s, 1H), 7.80 (d, 1H),7.648 (s, 1H), 7.49 (m, 1H), 7.40 (m, 2H), 7.15 (d, 1H), 2.433 (s, 3H).

Example 332

[1010]¹H NMR (acetone) δ 9.80 (br s, 1H), 8.162 (d, J=8.4 Hz, 1H), 7.735(d, J=2 Hz, 1H), 7.615 (dd, J=8.4, 2.1 Hz, 1H), 7.436 (d, J=2.2 Hz, 1H),7.358 (dt, J=10.5, 8.4 Hz, 1H), 7.292 (ddd, 1H), 7.224 (dd, J=8.4, 2.3Hz, 1H), 7.176 (d, J=8.4 Hz, 1H), 7.16 (m, 1H).

Example 338

[1011]2-Chloro-N-[3,5-dichloro-4-(3,4-dimethyl-phenylsulfanyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide(338)

[1012] A solution of aniline 319 (860 mg, 2.68 mmol) and3-chloro-4-trifluoromethylbenzene-sulfonylchloride (658 mg, 2.68 mmol)in pyridine (10 ml) was stirred at room temperature for 2-hr. Water wasadded to the reaction mixture, which was then acidified by 2N HCl.Reaction mixture was extracted twice with AcOEt. Organic layer waswashed by Brine, dried over MgSO₄ and concentrated. Crude residue waspurified by column chromatography (H/A=4/1, 80 g of silica gel) toafford compound 317 (591 mg, 41%) as a white solid.

[1013] 1H NMR (400 MHZ, DMSO-d₆) δ 2.11(3H,s), 2.13(3H,s), 6.78(1H,dd,J=2.1, 8.3 Hz), 6.81(1H,s), 7.01(1H,d, J=8.3 Hz), 7.30 (2H, s),7.98(2H,dd, J=2.1, 8.3 Hz), 8.18(1H,s), 8.35(1H, d, J=8.3 Hz), 11.6(1H,br s), mp 156-158° C. MS (M+H) 540.

Example 339

[1014] 3,5-Dichloro-4-(6-methyl-quinolin-3-yloxy)-phenylamine (339)

[1015] To a solution of3-(2,6-Dichloro-4-nitro-phenoxy)-6-methyl-quinoline (309) (1.30 g, 3.71mmol) and NH₄Cl (992 mg, 18.55 mmol) in EtOH/THF/H₂O=12 ml/12 ml/3 ml,was added Iron Powder (1.04 g, 18.55 mmol). The mixture was refluxed for4 hr. Insoluble materials were removed by Celite filtration. Thefiltrate was concentrated and sat NaHCO₃ was added to the residue, whichwas then extracted twice with AcOEt. Organic layer was washed withBrine, dried over anhydrous MgSO₄, and concentrated to afford compound339 (1.18 g, 98%).

[1016]¹H NMR (300 MHz, DMSO-d₆) δ 2.44 (3H, s), 5.75 (2H, br s), 6.77(2H, s), 7.27 (1H, d, J=2.8 Hz), 7.48 (1H, d, J=8.6 Hz), 7.67 (1H, s),7.89 (1H, d, J=8.6 Hz), 8.74 (1H, d, J=2.8 Hz).

Example 340

[1017] 2-Mercapto -4-methyl-benzothiazole (340)

[1018] The title compound was prepared using the method of example 239,starting with 2-bromo-4-methyl-phenylamine (Acros) (27.9 g),O-ethylxanthic acid, potassium salt (Lancaster, 54 g) in DMF (250 mL).The mercaptobenzothiazole 340 was obtained as an pale brown solid (27g). Recrystalization from CHCl₃ gave pinkish white crystals (20 g).

[1019]¹H NMR (DMSO-d₆) δ 7.499 (br s, 1H), 7.223 (d, J=8 Hz, 1H), 7.198(d, J=8 Hz, 1H), 2.342 (s, 3H).

Example 341

[1020] Compound 341 was prepared by the method of example 84.1 bycoupling thiol 340 (9.3 g) with 1,2,3,-trichloro-5-nitrobenzene (11.3 g)in DMF using NaH as base. Trituration with ether gave 341 (12.4 g) as ayellow solid.

[1021]¹H NMR (DMSO-d₆) δ 8.577 (s, 2H), 7.795 (br s, 1H), 7.736 (d,J=8.4 Hz, 1H), 7.303 (d, J=8.4 Hz, 1H), 2.405 (s, 3H).

Example 342

[1022] Reduction of compound 341 (12.4 g) with SnCl2 by the method ofexample 32 gave after trituration with methylene chloride, aniline 342(9 g) as a solid.

[1023]¹H NMR (DMSO-d₆) δ 7.709 (br s, 1H), 7.699 (d, J=8 Hz, 1H), 7.262(d, J=8 Hz, 1H), 6.859 (s, 2H), 6.45 (s, 2H), 2.384 (s, 3H).

Example 344

[1024] Compound 344 was prepared by the method of example 84.1 bycoupling thiol 245 (2.01 g) with 1,2,3,-trichloro-5-nitrobenzene (2.51 g) in DMF using NaH as base. Recrystalization with ether/hexane gavecompound 344 (3.2 g) as a yellow solid. Mp 116-118° C.

Example 345

[1025] Reduction of compound 344 (3.01 g) with SnCl2 by the method ofexample 32 gave aniline 345 (2.8 g) as a solid.

[1026]¹H NMR (DMSO-d₆) δ 7.772 (d, J=8.0 Hz, 1H), 7.630 (br s, 1H),7.155 (br d, J=8 Hz, 1H), 6.855 (s, 2H), 6.442 (s, 2H), 2.409 (s, 3H).MS (M+H) 341 Anal. calcd.: 49.27% C, 2.95% H, 8.21% N; found. 49.39% C,3.16% H, 7.98% N.

[1027] Example 342: X═Me, Y═H

[1028] Example 345: X═H, Y═Me

Examples 346-351

[1029] Sulfonylation of anilines 342 or 345 by the method of example 3gave the sulfonamides of Table 35. TABLE 35

Example MS # A B C D X V (M − H) 346 Cl H CF₃ H Me H 581 347 CF₃ H Cl HMe H 581 348 Cl H Cl Me Me H 561 349 Cl H CF₃ H H Me 581 350 Cl H Cl MeH Me 561 351 Cl H Me H H Me 527

Example 346

[1030]¹H NMR (DMSO-d₆) δ 11.90 (s, 1H), 8.416 (d, J=8.0 Hz, 1H), 8.228(br s, 1H), 8.024 (br d, J=8 Hz, 1H), 7.690 (m, 2H), 7.383 (s, 2H),7.265 (br d, J=8 Hz, 1H), 2.379 (s, 3H). MS (M−H) 580.8.

Example 347

[1031]¹H NMR(d₆-DMSO) δ 11.70-12.00 (1H, broad), 8.22 (1H, d, J=8.6 Hz),8.17 (1H, s), 8.08 (1H, d, J=8.5 Hz), 7.68-7.75 (2H, m),7.39 (2H, s),7.28 (1H, d, J=8.2 Hz), 2.39 (3H, s). MS (M−H) 580.8. mp 227.0° C. Anal.calcd.: C, 43.20, H, 2.07, N, 4.80; found C, 43.23, H, 1.97, N, 4.91.

Example 348

[1032]¹H NMR (DMSO-d₆) δ 11.71 (br s, 1H), 8.237 (br s, 1H), 7.915 (s,1H), 7.708 (s, 1H), 7.698 (d, J=8 Hz, 1H), 7.365 (s, 2H), 7.266 (dd,J=8, 1.6 Hz, 1H), 2.414 (s, 3H), 2.380 (s, 3H). MS (M−H) 560.8.

Example 349

[1033]¹H NMR (DMSO-d₆) δ 11.94 (br s, 1H), 8.416 (d, J=8.4 Hz, 1H),8.231 (d, J=1.6 Hz, 1H), 8.024 (dd, J=8.4, 1.6 Hz, 1H), 7.767 (d, J=8Hz, 1H), 7.628 (s, 1H), 7.382 (s, 2H), 7.185 (dd, J=8.4, 1.6 Hz, 1H),2.398 (s, 3H). MS (M−H) 580.8.

Example 350

[1034]¹H NMR (DMSO-d₆) δ 11.725 (br s, 1H), 8.236 (br s, 1H), 7.918 (s,1H), 7.785 (d, J=8 Hz, 1H), 7.637 (s, 1H), 7.363 (s, 2H), 7.183 (d, J=8Hz, 1H), 2.408 (s, 6H). MS (M−H) 560.9.

Example 351

[1035]¹H NMR (d₆-DMSO) δ 11.67 (1H, s), 8.12 (1H, d, J=8.1 Hz), 7.80(1H, d, J=8.2 Hz), 7.58-7.68 (2H, m), 7.46 (1H, d, J=8.1 Hz), 7.35 (2H,s), 7.20 (1H, d, J=8.2 Hz), 2.40 (6H, s). MS: (M−H) 526.8. mp 112.8° C.Anal. calcd.: 47.60% C, 2.85% H, 5.29% N; found 47.28% C, 2.98% H, 5.28%N.

Example 352

[1036] Aniline 342 was converted according to the method of example 34to afford the corresponding sulfonyl chloride 352 as a white solid.

[1037]¹H NMR (CDCl₃) δ 8.131 (s, 2H), 7.786 (d, J=8.4 Hz, 1H), 7.567 (brs, 1H), 7.28 (br d, J=8 Hz, 1H), 2.482 (s, 3H).

Example 353

[1038] Coupling of compound 352 (85 mg) with 3,4-dichloroaniline (42 mg)by the method of example 3 gave the sulfoamide 353 (76 mg) as a whitesolid.

[1039]¹H NMR (d₆-DMSO) δ 11.01 (1H, s), 8.04 (1H, s), 7.76 (1H, s), 7.72(1H, d, J=8.5 Hz), 7.62 (1H, d, J=8.7 Hz), 7.34 (1H, s), 7.29 (1H, d,J=7.6 Hz), 7.13-7.23 (1H, m), 2.40 (3H, s). MS (M−H) 546.8. mp 181.0° C.Anal. calcd.: 43.65% C, 2.20% H, 5.09% N; found 43.10% C, 2.21% H, 4.81%N.

Example 354

[1040] Coupling of compound 352 (85 mg) with 2,4-dichloroaniline (42 mg)by the method of example 3 gave after recrystalization from methanolwater, the sulfonamide 354 (38 mg) as a white solid.

[1041]¹H NMR (d₆-DMSO) δ 10.72 (1H, s), 7.96 (2H, s), 7.79 (1H, s),7.72-7.77 (2H, m), 7.47 (1H, dd, J=8.7, 2.4 Hz), 7.33 (1H, d, J=8.6 Hz),7.31 (1H, d, J=8.6 Hz), 2.41 (3H, s). MS (M+H) 548.9. mp 160.7° C. Anal.calcd.: 43.65% C, 2.20% H, 5.09% N; found 43.83% C, 2.19% H, 5.10% N.

[1042] The following examples illustrate the synthesis of compounds355-358.

Example 355

[1043] 2,3-dichloronitrobenzene (6.15 g, 32 mmol), methylaminehydrochloride (2.38 g, 35 mmol), triethylamine (9.8 mL, 71 mmol), andDMF (16 mL) were combined in a 100 mL round-bottomed flask and heated to90° C. overnight. The reaction was then cooled to room temperature anddumped over 600 mL of ice-water. The resulting orange solid wascollected by filtration and dried at the pump. Recrystallization fromhot hexanes yielded 3.2 g (53%) of compound 355 as bright orangecrystals.

[1044]¹H NMR ((d₆-DMSO) δ 7.75 (1H, dd); 7.62 (1H, dd); 6.76 (1H, t);6.63 (1H, broad s); 2.75 (3H, t).

Example 356

[1045] A round-bottomed flask was charged with 3.8 g (20 mmol) ofcompound 355, 22.9 g (102 mmol) of tin dichloride dihydrate, and 125 mLof EtOAc. This was heated to 75° C for 3.0 hours. The reaction wascooled to room temperature, diluted with 300 mL of EtOAc and washed with250 mL of 2N aqueous KOH solution followed by 200 mL of brine. Theorganics were dried over sodium sulfate and concentrated to a whiteamorphous solid 355 (2.9 g, 90%) that was used without furtherpurification (turned brown upon standing in air).

[1046]¹H NMR (d₆-DMSO) δ 6.68 (1H, t); 6.56 (2H, m); 4.98 (2H, broad s);3.76 (1H, broad s); 2.59 (3H, t).

Example 357

[1047] A round-bottomed flask was charged with 356 (1.0 g, 6.4 mmol),4-nitro-2-flourophenyl acetic acid (148) (1.4 g, 7.0 mmol), and 4Naqueous HCl (13 mL). This was refluxed overnight. The reaction was thencooled and basified with saturated aqueous sodium bicarbonate. Theorganics were extracted with methylene chloride, dried over Na₂SO₄, andconcentrated to a pink solid. This was recrystallized from methylenechloride and hexanes to yield compound 357 (1.4 g, 75%) as fluffycrystals.

[1048]¹H NMR (400 MHZ) (d₆-DMSO) δ 8.16 (1H, dd); 8.08 (1H, dd); 7.62(1H, t); 7.49 (1H, dd); 7.23 (1H, dd); 7.13 (1H, t); 4.48 (2H, s); 4.08(3H, s).

Example 358

[1049] Nitro compound 357 (1.3 g, 4.0 mmol) was reduced by the method ofexample 356 to give the aniline 358 (1.0 g, 86%) as off-white crystals.MS (M+H) 290.1.

Example 359-361

[1050] Aniline 358 was coupled with various sulfonyl chlorides by themethod of example 192 to give the sulfonamides illustrated in Table 35TABLE 36

EXAMPLE MS # A B C D yield (M −0 H) 359 Cl H Cl H 36% 496 360 H H —COMeH 50% 470 361 Me H Cl Me 60% 362 Cl H Cl Me 496% 

Example 359

[1051]¹H NMR (d₆-DMSO) δ 11.01 (1H, s); 8.07 (1H, d); 7.87 (1H, d); 7.63(1H, dd); 7.49 (1H, d); 7.22 (1H, d); 7.15 (2H, m); 6.89 (2H, m); 4.21(2H, s); 3.99 (3H, s). MS (M−H) 496.0.

Example 360

[1052]¹H NMR (d₆-DMSO) δ 10.78 (1H, s); 8.12 (2H, d); 7.94 (2H, d); 7.51(1H, d); 7.26 (1H, d); 7.17 (2H, t); 6.97 (2H, m); 4.24 (2H, s); 4.01(3H, s). MS (M−H) 470.1.

Example 361

[1053]¹H NMR (d₆-DMSO) δ 10.75 (1H, s); 7.91 (1H, s); 7.51 (2H, m); 7.26(1H, d); 7.16 (2H, dd); 6.88 (2H, t); 4.24 (2H, s); 4.01 (3H, s); 2.54(3H, s);2.34 (3H, s).

Example 362

[1054]¹H NMR (d₆-DMSO) δ 10.97 (1H, s); 8.10 (1H, s); 7.83 (1H, s); 7.52(1H, d); 7.27 (1H, d); 7.17 (2H, t); 6.94 (2H, m); 4.24 (2H, s); 4.01(3H, s); 2.38 (3H, s).

Example 363

[1055] This illustrates the preparation of 2,6-dichloro-benzothiazole(363).

[1056] 2-Amino-6-chlorobenzothiazole (15.7 g, 85 mmol) in H3PO4(85%)(470 ml) was heated to 100 degrees and dissolved. Then clearsolution was cooled and vigorously stirred by mechanical stirrer. NaNO₂(17.6 g, 255 mmol) in water (30 ml) was added slowly keeps thetemperature below 0 degrees. Separately a solution of CuSO₄/5H₂O(85 g),NaCl (107 g) in water (350 ml) was cooled to −5 degrees and stirred bymechanical stirrer. After Potassium Iodide Starch paper's color wasdisappeared Diazonium solution was keeping cold and added slowly to thecopper chloride solution with vigorous stirring. The reaction Mixturewas allowed to warm to room temperature. After 1-hour water (1L) andether (1L) were added to the reaction mixture and extracted twice.Organic layer was washed by water and dried over anhydrous MgSO₄ andconcentrated.Crude residue was purified by silica gel chromatography(H/A=4/1, 180 g of silica gel) to provide title compound 363 (7.46 g,48%).

Example 364

[1057] This illustrates the preparation of3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine.

[1058] To the solution of 4-amino-2,6-dichloro phenol (6 g, 26.5 mmol)and 2,6-dichlorobenzothiazole (363) (6 g, 29.4 mmol, 1.1 eq) in DMSO (25ml), was added K₂CO₃ (11 g, 80 mmol, 3.0 eq). The mixture was stirredand heated to 160 degree. After 5.5-hr water (20 ml) was added to thereaction mixture, which was neutralized with 2N HCl., and was extractedwith AcOEt three times. And the organic layer was washed with Brine andwas dried over anhydrous MgSO₄, and then concentrated. Crude residue waspurified by column chromatography (CHCl₃/Acetone=9/1, 180 g of silicagel) to afford3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (364) as ablack solid (4.52 g, 49%).

[1059]¹H NMR (300 MHz, DMSO-d₆) δ 5.86(2H, br s), 6.74(2H, s), 7.48(1H,dd, J=2.1, 5.7 Hz), 7.70(1H, d, 8.7 Hz), 8.10(1H, d, 2.1 Hz).

Example 365

[1060] This illustrates the preparation of2-Chloro-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(365).

[1061] A solution of3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (364) (2.0 g,5.79 mmol) and 3-chloro-4-trifluoromethylbenzenesulfonylchloride (1.7 g,6.08 mmol) in pyridine (10 ml) was stirred at room temperature. After3-hr water was added to the reaction mixture, which,was then acidify by2N HCl. Reaction mixture was extracted twice with AcOEt. Organic layerwas washed by brine, dried over MgSO₄ and concentrated. Crude residuewas purified by column chromatography (H/A=4/1, 80 g of silica gel) toafford title compound 365 (2.11 g, 65%) as a white solid. mp 82-84° C.

[1062]¹H NMR (400 MHz, DMSO-d₆) δ 7.32(2H, s), 7.46(1H, dd, J=2.2, 8.7Hz), 7.67(1H, d, J=8.7 Hz), 8.00(1H, d, 8.0 Hz), 8.14(1H, d, J=2.2 Hz),8.20(1H, s) 8.38(1H, d, J=8.3 Hz), 11.6(1H, br s). MS (M+H) 586.

Example 366

[1063] This illustrates the preparation of2,4-Dichloro-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]benzenesulfonamide(366).

[1064] A solution of3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (364) (2.0 g,5.79 mmol) and 2,4-dichloro benzenesulfonylchloride (1.5 g, 6.08 mmol)in pyridine (10 ml) was stirred at room temperature for 12-hr. Water wasadded to the reaction mixture, which was then acidified by 2N HCl.Reaction mixture was extracted twice with AcOEt. Organic layer waswashed by Brine, dried over MgSO₄ and concentrated. Crude residue waspurified by column chromatography (H/A=4/1, 80 g of silica gel) toafford title compound (366) (1.49 g, 46%) as a white solid. mp73-75° C.,

[1065]¹H NMR (300 MHz, DMSO-d₆) δ 7.29 (2H, s), 7.46 (1H, dd, J=2.2, 8.8Hz), 7.69 (1H, d, J=8.8 Hz), 7.71 (1H, dd, J=2.2, 8.4 Hz), 7.95 (1H, d,J=2.2 Hz), 8.14 (1H, d, J=2.2 Hz), 8.18 (1H, d, J=8.4 Hz), 11.5 (1H, brs). MS (M+H) 553.

Example 367

[1066] This illustrates the preparation of3,5-Dichloro-4-(6-methoxybenzothiazol-2-yloxy)phenylamine (367).

[1067] To a solution of 2-chloro-6-methoxybenzothiazole (prepared asdescribed by Weinstock et. al., J. Med. Chem.30: p1166 (1987)) and4-Amino-2,6-dichlorophenol 1.3 g (available from Tokyo Chemical IndustryCo., Ltd.) in DMSO(9 ml), was added K₂CO₃ 3.12 g. The mixture was heatedat 150 degree for 3 hr. The reaction mixture was purified by columnchromatography(silica gel, AcOEt:Hexane=1 :2) to provide the aniline 367(1.43 g, 56%). mp 158-160° C.

[1068] NMR(300 MHz/CDCl₃) δ 3.84(3H, s), 3.85(2H, brs), 6.69(2H, s)6.97(1H, dd, J=2.6 Hz, J=8.9 Hz), 7.18(1H, d, J=2.6 Hz),7.61(1H, d,J=8.9 Hz).

Example 368

[1069] This illustrates the preparation of2-Chloro-N-[3,5-dichloro-4-(6-methoxybenzothol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide(368). To a solution of3,5-dichloro-4-(6-methoxybenzothiazol-2-yloxy)phenylamine (367) (1.40 g)in pyridine (5 ml), was added 2-Chloro-4-trifluorobenzenesulfonamide1.15 g. The mixture was stirred at room temperature for 2 hr. Thereaction mixture was purified directly by column chromatography (silicagel, AcOEt:Hexane=1:3). The product was triturated by hexane to give thetitle compound 368 (1.97 g, 82%) as a colorless powder. mp 164-165° C.

[1070] NMR (300 MHz/DMSO-d6) δ 3.79(3H, s), 7.00(1H, dd, J=2.9 Hz, J=8.8Hz), 7.31(2H, s), 7.55(1H, d, J=8.8 Hz), 7.58(1H, d, J=2.9 Hz), 8.00(1H, dd, J=1.5 Hz, J=8.1 Hz), 8.20 (1H, d, J=1.5 Hz), 8.37(1H, d, J=8.1Hz), 11.59(1H, brs). MS (M+H) 583.

Examples 369-370

[1071] The examples illustrated in Table 37, were prepared from aniline75 and the corresponding sulfonyl chlorides by the method of procedure3. The compounds were purified by chromatography on silica gel. TABLE 37

Example MS # A B C D (M − H) 369 Cl H Cl H 466 370 H Cl Cl H 466 371 MeH Cl Me 460 372 Cl H Cl Me 480

Example 369

[1072]¹H NMR (d6-acetone) δ 9.54 (br s, 1H), 8.82 (br s, 1H), 8.446 (d,J=8.8 Hz, 1H), 8.129 (d, J=8.4 Hz, 1H), 7.763 (d, J=2 Hz, 1H), 7.602(dd, J=8.4, 2 Hz, 1H), 7.428 (m, 2H), 7.327 (dd, J=9.2, 2.4 Hz, 1H),7.252 (td, J=7.6, 1.2 Hz, 1H), 7.17 (td, J=8, 1.2 Hz, 1H). MS (M−H)466.0.

Example 370

[1073]¹H NMR (d6-DMSO) δ 10.643 (br s, 1H), 9.954 (br s, 1H), 7.983 (d,J=2 Hz, 1H), 7.934 (br d, J=8 Hz, 1H), 7.885 (d, J=8.4 Hz, 1H), 7.717(dd, J=8.4, 2.4 Hz, 1H), 7.454 (d, J=8 Hz, 1H), 7.360 (br d, J=7.6 Hz,1H), 7.226 (d, J=2 Hz, 1H), 7.194 (t, J=8 Hz, 1H), 7.142 (dd, J=8.8, 2Hz, 1H), 7.106 (t, J=8 Hz, 1H). MS (M−H) 466.0.

Example 371

[1074]¹H NMR (d6-acetone) δ 9.31 (br s, 1H), 8.80 (br s, 1H), 8.403 (d,J=8 Hz, 1H), 7.928 (s, 1H), 7.45-7.35 (m, 4H), 7.3-7.2 (m, 2H), 7.164(br t, J=8 Hz, 1H), 2.64 (s, 3H), 2.387 (s, 3H). MS (M−H) 460.0.

Example 372

[1075]¹H NMR (d6-acetone) δ 9.48 (br s, 1H), 8.82 (br s, 1H), 8.064 (s,1H), 7.707 (s, 1H), 7.45-7.40 (m, 4H), 7.335 (dd, J=8.8, 2 HZ, 1H),7.252 (td, J=7.6, 1.2 Hz, 1H), 7.19 (td, J=8, 1.2 Hz, 1H) 2.425 (s, 3H).MS (M−H) 479.9.

Example 373

[1076] Using methods similar to Lehmann, et al., ibid., selectedcompounds exhibited the following IC₅₀ values in a PPARγ ligand bindingassay utilizing [³H]-BRL 49653 as the radioligand. IC₅₀ values aredefined as the concentration of test compounds required to reduce by 50%the specific binding of [³H]-BRL 49653 and are represented by (+)<30 μM;(++)<10 μM; (+++)<1 μM. TABLE 38 Compound IC₅₀(μM) 4.1 +++ 16.1 +++ 27.3++ 27.5 ++ 49.1 +++ 50.1 +++ 72.2 ++ 72.3 +++ 72.4 ++ 73.4 +++ 73.5 +++73.6 +++ 73.7 +++ 73.8 +++ 73.9 +++ 79.5 +++ 86 +++ 87.3 +++ 95 +++ 97+++ 108.4 +++ 158 +++ 160 +++ 178 +++ 179 +++ 219 +++ 233 +++ 290 +++292 +++ 349 +++ 364 ++ 365 ++ 368 +++

Example 374

[1077] Selected compounds were administered to KK-Ay mice as a 0.018%(30 mg/kg) dietary admixture in powdered diet and evaluated foranti-diabetic efficacy as described (T. Shibata, K. Matsui, K. Nagao, H.Shinkai, F. Yonemori and K. Wakitani 1999; European Journal ofPharmacology 364:211-219). The change in serum glucose levels comparedto uncontrol animals is exemplified in Table 39. TABLE 39 Example # KKAyGlucose 87.3 ++ 178 ++ 179 ++ 219 + 233 − 364 + 365 ++

[1078] All publications and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

What is claimed is:
 1. A compound having the formula:

wherein Ar¹ is a substituted or unsubstituted aryl; X is a divalentlinkage selected from the group consisting of (C₁-C₆)alkylene,(C₁-C₆)alkylenoxy, (C₁-C₆)alkylenamino, (C₁-C₆)alkylene—S(O)_(k)—, —O—,—C(O)—, —N(R¹¹)—, —N(R¹¹)C(O)—, —S(O)_(k)— and a single bond, whereinR¹¹ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and aryl(C₁-C₄)alkyl; and the subscriptk is an integer of from 0 to 2; Y is a divalent linkage selected fromthe group consisting of alkylene, —O—, —C(O)—, —N(R¹²)—S(O)_(m)—,—N(R¹²)—S(O)_(m)—N(R¹³)—, —N(R¹²)C(O)—, —S(O)_(n)— and a single bond,wherein R¹² and R¹³ are members independently selected from the groupconsisting of hydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl andaryl(C₁-C₄)alkyl; and the subscripts m and n are independently integersof from 0 to 2; R¹ is a member selected from the group consisting ofhydrogen, (C₂-C₈)heteroalkyl, aryl, aryl(C₁-C₄)alkyl, halogen, cyano,nitro, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—OR¹⁷, —O—C(O)—R¹⁷,—O—C(O)—NR¹⁵R¹⁶, —N(R¹⁴)—C(O)—NR¹⁵R¹⁶, —N(R¹⁴)—C(O)—R¹⁷ and—N(R¹⁴)—C(O)—OR¹⁷; wherein R¹⁴ is a member selected from the groupconsisting of hydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, aryl andaryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶ are members independently selected fromthe group consisting of hydrogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,aryl, and aryl(C₁-C₄)alkyl, or taken together with the nitrogen to whicheach is attached form a 5-, 6- or 7-membered ring; R¹⁷ is a memberselected from the group consisting of (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,aryl and aryl(C₁-C₄)alkyl; the subscript p is an integer of from 0 to 3;and the subscript q is an integer of from 1 to 2; and R² is asubstituted or unsubstituted aryl; and R³ is a member selected from thegroup consisting of halogen, cyano, nitro and (C₁-C₈)alkoxy.
 2. Acompound of claim 1, wherein Ar¹ is a substituted or unsubstituted arylselected from the group consisting of pyridyl, phenyl, naphthyl,isoquinolinyl, benzthiazolyl, benzoxazolyl and benzimidazolyl; with theproviso that when Ar¹ is substituted or unsubstituted benzthiazolyl,then X is —S(O)_(k)—; and R² is a substituted or unsubstituted arylselected from the group consisting of phenyl, pyridyl, naphthyl andpyridazinyl.
 3. A compound of claim 2, wherein Ar¹ is a substituted orunsubstituted phenyl group.
 4. A compound of claim 3, represented by aformula selected from the group consisting of


5. A compound of claim 3, represented by a formula selected from thegroup consisting of


6. A compound of claim 5, wherein X is a divalent linkage selected fromthe group consisting of —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)— and —S—;wherein R¹¹ is a member selected from the group consisting of hydrogenand (C₁-C₈)alkyl; Y is a divalent linkage selected from the groupconsisting of —N(R¹²)—S(O)₂—, wherein R¹² is a member selected from thegroup consisting of hydrogen and (C₁-C₈)alkyl; R¹ is a member selectedfrom the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and —N(R¹⁴)—C(O)—R¹⁷;wherein R¹⁴ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl, hetero(C₁-C₈)alkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from the group consisting ofhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl, or taken together withthe nitrogen to which each is attached form a 5-, 6- or 7-membered ring;R¹⁷ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is an integer offrom 0 to 2; and the subscript q is 2; and R² is a substituted orunsubstituted phenyl; and R³is a member selected from the groupconsisting of halogen and (C₁-C₈)alkoxy.
 7. A compound of claim 6,wherein X is —O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selectedfrom the group consisting of halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,(C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and—S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0 to 3 substitutentsselected from the group consisting of halogen, —OCF₃, —OH,—O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂;and R³ is selected from the group consisting of halogen, methoxy andtrifluoromethoxy.
 8. A compound of claim 7, wherein Ar¹ is a phenylgroup having from 1 to 3 substituents selected from the group consistingof halogen, —OCF₃, —OH, —O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl and —NO₂; R¹is a member selected from the group consisting of halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² is a phenyl group having from 0to 3 substitutents selected from the group consisting of halogen, —OCF₃,—OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and—NH₂; and R³ is selected from the group consisting of halogen, methoxyand trifluoromethoxy.
 9. A compound of claim 2, wherein Ar¹ is asubstituted or unsubstituted pyridyl group.
 10. A compound of claim 9,represented by a formula selected from the group consisting of


11. A compound of claim 10, represented by a formula selected from thegroup consisting of


12. A compound of claim 11, wherein X is a divalent linkage selectedfrom the group consisting of —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)— and—S—; wherein R¹¹ is a member selected from the group consisting ofhydrogen and (C₁-C₈)alkyl; Y is a divalent linkage selected from thegroup consisting of —N(R¹²)—S(O)₂—, wherein R¹² is a member selectedfrom the group consisting of hydrogen and (C₁-C₈)alkyl; R¹ is a memberselected from the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and —N(R¹⁴)—C(O)—R¹⁷;wherein R¹⁴ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl, hetero(C₁-C₈)alkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from the group consisting ofhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl, or taken together withthe nitrogen to which each is attached form a 5-, 6- or 7-membered ring;R¹⁷ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is an integer offrom 0 to 2; and the subscript q is 2; and R² is a substituted orunsubstituted phenyl; and R³is a member selected from the groupconsisting of halogen and (C₁-C₈)alkoxy.
 13. A compound of claim 12,wherein X is —O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selectedfrom the group consisting of halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,(C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and—S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0 to 3 substitutentsselected from the group consisting of halogen, —OCF₃, —OH,—O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂;and R³ is selected from the group consisting of halogen, methoxy andtrifluoromethoxy.
 14. A compound of claim 13, wherein Ar¹ is a pyridylgroup having from 1 to 3 substituents selected from the group consistingof halogen, —OCF₃, —OH, —O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl and —NO₂; R¹is a member selected from the group consisting of halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² is a phenyl group having from 0to 3 substitutents selected from the group consisting of halogen, —OCF₃,—OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and—NH₂; and R³ is selected from the group consisting of halogen, methoxyand trifluoromethoxy.
 15. A compound of claim 2, wherein Ar¹ is asubstituted or unsubstituted naphthyl group.
 16. A compound of claim 15,represented by a formula selected from the group consisting of


17. A compound of claim 16, represented by a formula selected from thegroup consisting of


18. A compound of claim 17, wherein X is a divalent linkage selectedfrom the group consisting of —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)— and—S—; wherein R¹¹ is a member selected from the group consisting ofhydrogen and (C₁-C₈)alkyl; Y is a divalent linkage selected from thegroup consisting of —N(R¹²)—S(O)₂—, wherein R¹² is a member selectedfrom the group consisting of hydrogen and (C₁-C₈)alkyl; R¹ is a memberselected from the group consisting of hydrogen, halogen, C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵ R¹⁶, —O—C(O)—R¹⁷, and —N(R¹⁴)—C(O)—R¹⁷;wherein R¹⁴ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl, hetero(C₁-C₈)alkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from the group consisting ofhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl, or taken together withthe nitrogen to which each is attached form a 5-, 6- or 7-membered ring;R¹⁷ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is an integer offrom 0 to 2; and the subscript q is 2; and R² is a substituted orunsubstituted phenyl; and R³ is a member selected from the groupconsisting of halogen and (C₁-C₈)alkoxy.
 19. A compound of claim 18,wherein X is —O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selectedfrom the group consisting of halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,(C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and—S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0 to 3 substitutentsselected from the group consisting of halogen, —OCF₃, —OH,—O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂;and R³ is selected from the group consisting of halogen, methoxy andtrifluoromethoxy.
 20. A compound of claim 19, wherein Ar¹ is a naphthylgroup having from 1 to 3 substituents selected from the group consistingof halogen, —OCF₃, —OH, —O(C₁-C₆)alkyl, —CF₃, (C₁-C₈)alkyl and —NO₂; R¹is a member selected from the group consisting of halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² is a phenyl group having from 0to 3 substitutents selected from the group consisting of halogen, —OCF₃,—OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and—NH₂; and R³ is selected from the group consisting of halogen, methoxyand trifluoromethoxy.
 21. A compound of claim 2, wherein Ar¹ is asubstituted or unsubstituted isoquinolinyl group.
 22. A compound ofclaim 21, represented by a formula selected from the group consisting of


23. A compound of claim 22, represented by a formula selected from thegroup consisting of


24. A compound of claim 23, wherein X is a divalent linkage selectedfrom the group consisting of —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)— and—S—; wherein R¹¹ is a member selected from the group consisting ofhydrogen and (C₁-C₈)alkyl; Y is a divalent linkage selected from thegroup consisting of —N(R¹²)—S(O)₂—, wherein R¹² is a member selectedfrom the group consisting of hydrogen and (C₁-C₈)alkyl; R¹ is a memberselected from the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR ¹⁵R¹⁶,—S(O)_(p)—R⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and —N(R¹⁴)—C(O)—R¹⁷;wherein R¹⁴ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl, hetero(C₁-C₈)alkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from the group consisting ofhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl, or taken together withthe nitrogen to which each is attached form a 5-, 6- or 7-membered ring;R¹⁷ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is an integer offrom 0 to 2; and the subscript q is 2; and R² is a substituted orunsubstituted phenyl; and R³is a member selected from the groupconsisting of halogen and (C₁-C₈)alkoxy.
 25. A compound of claim 24,wherein X is —O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selectedfrom the group consisting of halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,(C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and—S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0 to 3 substitutentsselected from the group consisting of halogen, —OCF₃, —OH,—O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂;and R³ is selected from the group consisting of halogen, methoxy andtrifluoromethoxy.
 26. A compound of claim 25, wherein Ar¹ is aisoquinolinyl group having from 1 to 3 substituents selected from thegroup consisting of halogen, —OCF₃, —OH, —O(C₁-C₆)alkyl, —CF₃,(C₁-C₈)alkyl and —NO₂; R¹ is a member selected from the group consistingof halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² is aphenyl group having from 0 to 3 substitutents selected from the groupconsisting of halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl,—CN, —CF₃, (C₁-C₈)alkyl and —NH₂; and R³ is selected from the groupconsisting of halogen, methoxy and trifluoromethoxy.
 27. A compound ofclaim 2, wherein Ar¹ is a substituted or unsubstituted benzoxazolylgroup.
 28. A compound of claim 27, represented by a formula selectedfrom the group consisting of


29. A compound of claim 28, represented by a formula selected from thegroup consisting of


30. A compound of claim 29, wherein X is a divalent linkage selectedfrom the group consisting of —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)— and—S—; wherein R¹¹ is a member selected from the group consisting ofhydrogen and (C₁-C₈)alkyl; Y is a divalent linkage selected from thegroup consisting of —N(R¹²)—S(O)₂—, wherein R¹² is a member selectedfrom the group consisting of hydrogen and (C₁-C₈)alkyl; R¹ is a memberselected from the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and —N(R¹⁴)—C(O)—R¹⁷;wherein R¹⁴ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl, hetero(C₁-C₈)alkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from the group consisting ofhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl, or taken together withthe nitrogen to which each is attached form a 5-, 6- or 7-membered ring;R¹⁷ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is an integer offrom 0 to 2; and the subscript q is 2; and R² is a substituted orunsubstituted phenyl; and R³ is a member selected from the groupconsisting of halogen and (C₁-C₈)alkoxy.
 31. A compound of claim 30,wherein X is —O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selectedfrom the group consisting of halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,(C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R⁴ and—S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0 to 3 substitutentsselected from the group consisting of halogen, —OCF₃, —OH,—O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH_(2;)and R³ is selected from the group consisting of halogen, methoxy andtrifluoromethoxy.
 32. A compound of claim 31, wherein Ar¹ is abenzoxazolyl group having from 1 to 3 substituents selected from thegroup consisting of halogen, —OCF₃, —OH, —O(C₁-C₆)alkyl, —CF₃,(C₁-C₈)alkyl and —NO₂; R¹ is a member selected from the group consistingof halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² is aphenyl group having from 0 to 3 substitutents selected from the groupconsisting of halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl,—CN, —CF₃, (C₁-C₈)alkyl and —NH₂; and R³ is selected from the groupconsisting of halogen, methoxy and trifluoromethoxy.
 33. A compound ofclaim 2, wherein Ar¹ is a substituted or unsubstituted benzimidazolylgroup.
 34. A compound of claim 33, represented by a formula selectedfrom the group consisting of


35. A compound of claim 34, represented by a formula selected from thegroup consisting of


36. A compound of claim 35, wherein X is a divalent linkage selectedfrom the group consisting of —CH₂—, —CH(CH₃)—, —O—, —C(O)—, —N(R¹¹)— and—S—; wherein R¹¹ is a member selected from the group consisting ofhydrogen and (C₁-C₈)alkyl; Y is a divalent linkage selected from thegroup consisting of —N(R¹²)—S(O)₂—, wherein R¹² is a member selectedfrom the group consisting of hydrogen and (C₁-C₈)alkyl; R¹ is a memberselected from the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶,—S(O)_(p)—R¹⁴, —S(O)_(q)—NR¹⁵R¹⁶, —O—C(O)—R¹⁷, and —N(R¹⁴)—C(O)—R¹⁷;wherein R¹⁴ is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl, hetero(C₁-C₈)alkyl, aryl and aryl(C₁-C₄)alkyl; R¹⁵ and R¹⁶are members independently selected from the group consisting ofhydrogen, (C₁-C₈)alkyl and (C₂-C₈)heteroalkyl, or taken together withthe nitrogen to which each is attached form a 5-, 6- or 7-membered ring;R¹⁷is a member selected from the group consisting of hydrogen,(C₁-C₈)alkyl and (C₂-C₈)heteroalkyl; the subscript p is an integer offrom 0 to 2; and the subscript q is 2; and R² is a substituted orunsubstituted phenyl; and R³ is a member selected from the groupconsisting of halogen and (C₁-C₈)alkoxy.
 37. A compound of claim 36,wherein X is —O—, —NH— or —S—; Y is —NH—SO₂—; R¹ is a member selectedfrom the group consisting of halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,(C₁-C₈)alkoxy, —C(O)R¹⁴, —CO₂R¹⁴, —C(O)NR¹⁵R¹⁶, —S(O)_(p)—R¹⁴ and—S(O)_(q)—NR¹⁵R¹⁶; R² is a phenyl group having from 0 to 3 substitutentsselected from the group consisting of halogen, —OCF₃, —OH,—O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl, —CN, —CF₃, (C₁-C₈)alkyl and —NH₂;and R³ is selected from the group consisting of halogen, methoxy andtrifluoromethoxy.
 38. A compound of claim 37, wherein Ar¹ is abenzimidazolyl group having from 1 to 3 substituents selected from thegroup consisting of halogen, —OCF₃, —OH, —O(C₁-C₆)alkyl, —CF₃,(C₁-C₈)alkyl and —NO₂; R¹ is a member selected from the group consistingof halogen, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl and (C₁-C₈)alkoxy; R² is aphenyl group having from 0 to 3 substitutents selected from the groupconsisting of halogen, —OCF₃, —OH, —O(C₁-C₈)alkyl, —C(O)—(C₁-C₈)alkyl,—CN, —CF₃, (C₁-C₈)alkyl and —NH_(2;) and R³ is selected from the groupconsisting of halogen, methoxy and trifluoromethoxy.
 39. A compound ofclaim 1, selected from the group consisting of


40. A compound of claim 1, selected from the group consisting of


41. A compound of claim 1, selected from the group consisting of


42. A compound of claim 1, selected from the group consisting of:


43. A compound of claim 1, selected from the group consisting of:


44. A compound of claim 1, selected from the group consisting of:


45. A compound of claim 1, selected from the group consisting of:


46. A composition comprising a pharmaceutically acceptable excipient anda compound of any of claims 1-45.
 47. A method for modulating conditionsassociated with metabolic or inflammatory disorders in a host, saidmethod comprising administering to said host an efficacious amount of acompound of any of claims 1-45.
 48. A method in accordance with claim47, wherein said host is a mammal selected from the group consisting ofhumans, dogs, monkeys, mice, rats, horses and cats.
 49. A method inaccordance with claim 47, wherein said administering is oral.
 50. Amethod in accordance with claim 47, wherein said administering istopical.
 51. A method in accordance with claim 47, wherein saidadministering is prophylactic to prevent the onset of a PPARγ-mediatedcondition.
 52. A method in accordance with claim 47, wherein saiddisorders are selected from the group consisting of NIDDM, obesity,hypercholesterolemia and other lipid-mediated diseases, and inflammatoryconditions.
 53. A method in accordance with claim 47, wherein saidadministering is parenteral.
 54. A method in accordance with claim 47,wherein said metabolic disorders are mediated by PPARγ.